Send O de s o Rep in s o [email p o ec ed]
122 The Open Oph halmology Jou nal, 2017, 11, 122-142
1874-3641/17 2017 Ben ham Open
The Open Oph halmology Jou nal
Con en lis a ailable a : www.ben hamopen.com/TOOPHTJ/
DOI: 10.2174/1874364101711010122
REVIEW ARTICLE
Many Faces o Renin-angio ensin Sys em - Focus on Eye
Me i Holappa1, Heikki Vapaa alo2 and Anu Vaajanen3,4,*
1 BioMediTech, Uni e si y o Tampe e, Tampe e, Finland
2Medical Facul y, Depa men o Pha macology, Uni e si y o Helsinki, 00014 Helsinki, Finland
3Depa men o Oph halmology, Tampe e Uni e si y Hospi al, Tampe e, Finland
4SILK, Depa men o Oph halmology, School o Medicine, Uni e si y o Tampe e, Tampe e, Finland
Recei ed: Ap il 16, 2017 Re ised: May 17, 2017 Accep ed: May 25, 2017
Abs ac : The enin-angio ensin sys em (RAS), ha is known o i s ole in he egula ion o blood p essu e as well as in luid and
elec oly e homeos asis, comp ises dozens o angio ensin pep ides and pep idases and a leas six ecep o s. Six cen al componen s
cons i u e he wo main axes o he RAS cascade. Angio ensin (1-7), an angio ensin con e ing enzyme 2 and Mas ecep o axis
(ACE2-Ang(1-7)-MasR) coun e balances he ha m ul e ec s o he angio ensin II, angio ensin con e ing enzyme 1 and angio ensin
II ype 1 ecep o axis (ACE1-AngII-AT1R) Whe eas sys emic RAS is an impo an ac o in blood p essu e egula ion, issue-
speci ic egula o y sys em, esponsible o long e m egional changes, ha has been ound in a ious o gans. In o he wo ds, RAS is
no only endoc ine bu also complica ed au oc ine sys em. The human eye has i s own in aocula RAS ha is p esen e.g. in he
s uc u es in ol ed in aqueous humo dynamics. Local RAS may hus be a a ge in he de elopmen o new an i-glaucoma ous
d ugs. In his e iew, we i s desc ibe he sys emic RAS cascade and hen he local ocula RAS especially in he an e io pa o he
eye.
Keywo ds: ACE1, ACE2, Angio ensin II, Angio ensin (1-7), Eye, Glaucoma, In aocula p essu e, Mas ecep o , Renin-angio ensin
sys em.
INTRODUCTION
Glaucoma, known o i s des uc i e e ec s on he op ic ne e axons and e inal ganglion cells, is one o he leading
causes o blindness wo ldwide. In he nex h ee yea s, app oxima ely 80 million people a ound he wo ld a e p edic ed
o be diagnosed wi h glaucoma [1]. This numbe is likely o be e en highe due o he ac ha glaucoma can be
asymp oma ic o a long ime which makes i di icul o de ec un il i is se e e [2, 3]. Glaucoma is a mul i ac o ial
op ic neu opa hy ha can be oughly di ided in o wo ca ego ies: open-angle glaucoma (POAG) and angle-closu e
glaucoma, bo h o which can cause isual ield de ec s and i e e sible ision loss [4 - 10].
While many gene ic and biological isk ac o s ha e been iden i ied, such as age, ace and diabe es, he mos
undamen al eason why a pa ien is diagnosed wi h glaucoma is inc eased in aocula p essu e (IOP) [6, 10 - 13]. The
exac unde lying mechanism o glaucoma de elopmen is s ill poo ly known which makes i di icul o de elop
e ec i e he apies o his des uc i e disease [14, 15]. As o oday, he only ea men demons a ed o be e ec i e o
educe disease p og ess is o lowe IOP [16, 17]. Tha is o say, dec ease o IOP by 30% educes disease p og ess [18,
19]. In addi ion o he classical RAS ha egula es blood p essu e (BP), luid olume as well as elec oly e balance and
is also in ol ed in in lamma ion, local issue-speci ic RA-sys ems ha e been desc ibed in nume ous o gans including
he human eye [20 - 24]. While he pa hological mechanisms a molecula le el a e no ye well unde s ood, local ocula
RAS seems o ha e a ole in ocula pa hology and i has been associa ed o glaucoma and o he eye diso de s such as
diabe ic e inopa hy (DR), age- ela ed macula degene a ion (AMD) and e inopa hy o p ema u i y (ROP) [22, 25]. In
his e iew, we desc ibe he local ocula RAS cascade and concen a e on i s po en ial ole in he egula ion o
* Add ess co espondence o his au ho a he Depa men o Oph halmology, Tampe e Uni e si y Hospi al, P.O. Box 2000, 33521 Tampe e,
Finland, Tel +358-3-31164852, E-mail: [email p o ec ed]
RAS in he Eye The Open Oph halmology Jou nal, 2017, Volume 11 123
IOP while keeping he ocus on he an e io pa o he eye. A comp ehensi e su ey o li e a u e on PubMed was
pe o med o collec he li e a u e and e en ually 258 a icles we e chosen based on hei ele ance. The ollowing
keywo ds we e used and combined o na ow down he li e a u e: IOP (41729), RAS (29132), issue RAS (6080),
angio ensin (116858), angio ensin I (8316), angio ensin II (59230), angio ensin (1-7) (1278), angio ensin (1-9) (73),
angio ensin (3-4) (10) angio ensin con e ing enzyme 1 (238) and -2 (1453), Mas ecep o (445), angio ensin ecep o
(17975), eye disease (5611), glaucoma (59565), diabe ic e inopa hy (DR) (26740), e inopa hy o p ema u i y (ROP)
(6638) and age- ela ed macula degene a ion (AMD) (13303).
RENIN-ANGIOTENSIN SYSTEM
Ci cula ing Ras
The enin-angio ensin sys em is one o he oldes and mos s udied pep ide cascades known oday. The esea ch
concen a ing on RAS s a ed, in 1898, in Finland when Robe Tige s ed and Pe Be gman iden i ied a enal BP
ele a ing subs ance: enin [20, 26, 27]. O e 40 yea s la e , mo e componen s o he RAS cascade we e iden i ied, one
being he angio ensin pep ide, i s named as angio onin, ha B aun-Menéndez and Page epo ed o be o med om
angio ensinogen by enin, an enzyme o igina ed in he kidney [28 - 30]. 1970 was an impo an yea in he RAS
esea ch as i s ole in BP and luid balance egula o was unde s ood which led o he de elopmen o he i s
an ihype ensi e medica ions such as cap op il ha blocks he o ma ion o Ang II by inhibi ing ACE1 [20, 28]. La e
mo e an ihype ensi e d ugs we e designed and de eloped, one o which was Ang II ype 1 ecep o blocke (ARB) ha
blocks he asocons ic i e e ec s o Ang II h ough i s main ecep o [31].
Mul iple pep ides, enzymes and ecep o s ha e been iden i ied since he i s clue o he exis ence o RAS. One o
he impo an and ai ly ecen indings was he iden i ica ion o a new ecep o ype: MasR whose ac i i ies, such as
asodila a ion, an i ib osis and an ip oli e a ion, a e opposi e o hose o angio ensin II ype 1 ecep o (AT1R). This
disco e y led o he di ision o RAS in o wo cen al axes: ACE1-Ang II-AT1R and ACE2-Ang(1-7)-MasR gi ing
an ihype ensi e d ug de elopmen new angles o ocus on [32 - 34] as ch onic imbalances o hese main axes can
po en ially lead o pa hological e en s o e.g. enal, ca dio ascula and cen al ne ous sys em [35]. In ime, RAS has
uly e ol ed om simple linea pa hway, ha ing only one known subs a e, wo p o eases, wo pep ides and one
ecep o , in o a complex cascade consis ing o mul iple media o s, unc ionally e sa ile enzymes and a ious ecep o s
ha a e ac i a ed by se e al angio ensin pep ides [36 - 40]. Figu e 1 shows he ull ex en o he RAS cascade known
oday.
Fig. (1). The enin-angio ensin sys em. The wo main axes o RAS a e highligh ed wi h colo s. ACE2-Ang(1-7)-MasR axis ( ed
lines) coun e balances he ha m ul e ec s o he ACE1-Ang II-AT1R axis (blue lines). ACE1: Angio ensin-con e ing enzyme 1;
ACE2: Angio ensin-con e ing enzyme ela ed ca boxypep idase; Ang I, II, III, IV: Angio ensin I, II, III, IV; Ang A: Angio ensin A;
AT1R, -2R, -4R: Angio ensin II ype 1, -2, -4 ecep o ; AP: Aminopep idase (-A, -N, -M, -B); B1/B2: B adykinin ecep o s; CAGE:
Chymos a in-sensi i e Ang II gene a ing enzyme; CP: Ca boxypep idase; EP: Endopep idase; Mas ecep o : Ang(1-7) ecep o ype;
NEP: Nep ilysin; PEP: P olyl-endopep idase; PCP: P olyl-ca boxypep idase; PA: Tissue- ype plasminogen ac i a o . In angio ensin
pep ides he numbe s in pa en hesis e e s o he numbe s o amino acid esidues. The igu e is upda ed om Vaajanen e al. [41].
CP/NEP
AP
ACE1 ACE1
NEP
Ca hepsin G
Tonin, -PA
T ypsin
Chymo ypsin
Angio ensinogen
enin
P o enin
Ang(1-9)
Ang III
[Ang(2-8)]
Ang(2-10)
Ang(1-5)
Ang(1-4)
A(5
8
)
Ang(1-7)
Kininogen
B adykinin
Inac i e
pep ides
P ocon e ase
Ca hepsin B
ACE1, CAGE
Chymase
Ca hepsin G
AP-A
ACE1
AP
-
NAP
-
MAP
-
B
AP-A
ACE1, NEP
Kallik ein
ACE2
PEP
NEP
ACE2
PC-P
Ang(1-12
)
ACE2
CP-A
Ca hep-
sin A
Ang II
[A (1
8)]
Ang I
[Ang(1-10)]
Ang(1-12
)
Deca boxylase
AP
EP
AP
Ang IV
[Ang(3-8)]
Ang(3-4)
Ang(3-7)
Ang(2-7)
Ang(5
-
8
)
Ang(5-7)
Alamandine
AP
N, AP
M, AP
B
AP-N
Vasodila a ion
Cell p oli e a ion
In lamma ion
Neu onal de elopmen
Vasocons ic ion
Hype ophy
Fib osis
Apop osis
Vasocons ic ion
Cell p oli e a ion
Fluid olume
homeos asis
Fib osis
AT1R AT2R
Vasodila a ion
An ip oli e a ion
P oapop osis
P ena al de elopmen
CP AP
PEP
MasR
Vasodila a ion
An ip oli e a ion
An i ib osis
Fluid olume
homeos asis
(P)RR AT4R B1/B2
ecep o
Vasodila a ion
P oli e a ion
Cy okine elease
Senso y ac i a ion
AP
AP
Ang A
ACE2
[Ang(1
-
8)]
124 The Open Oph halmology Jou nal, 2017, Volume 11 Holappa e al.
The classical RAS cascade s a s wi h highly speci ic aspa yl p o ease enin ha clea es he pep ide bond be ween
Leu10 and Val11 a he amino e minus o angio ensinogen (AGT), a 225 amino acids long α-glycop o ein, o o m
angio ensin I (Ang I) [28, 42, 43]. AGT is mainly syn hesized and eleased om li e bu o he o gans such as hea ,
kidney and adipose issue can also p oduce i [44]. In lamma ion, insulin and es ogens among o he hings can
s imula e he syn hesis o AGT [42]. Renin is mainly syn hesized in kidney as an inac i e p o enin ha is ac i a ed by
ei he ca hepsin B o p ocon e ase and sec e ed om he jux aglome ula appa a us [28, 42, 43] in esponse o ei he
dec eased a e ial BP, dec eased sodium le els o inc eased ac i i y o sympa he ic ne ous sys em [45 - 47]. Bo h enin
and p o enin can bind o (p o) enin ecep o ((P)RR) and hus media e asocons ic i e e ec s [42, 48].
Ang I, a weak p oho mone and asocons ic o can be u he clea ed o o m Ang II. Di e en enzymes can o m
Ang II om Ang I: e.g. ACE1, onin [49], ypsin [50], kallik ein [51], ca hepsin G [52] and chymase [53 - 55]. ACE1
is p esen in many issues as well as in biological luids e.g. in plasma [56 - 58]. In o de o wo k, ACE1 needs Zn2+ in
complex wi h ac i a ed wa e molecule in i s ac i e si e [59] and chlo ide o imp o e subs a e binding [60]. This main
enzyme ac ing on Ang I, emo es wo amino acids (His-Leu) om he ca boxyl e minus o Ang I o o m one o he
cen al pep ides o RAS cascade: Ang II. In addi ion o being an impo an enzyme in RAS, ACE1 also ac s in
kallik ain-kinin sys em [42, 45]. O he enzymes men ioned abo e a e ega ded as al e na i e pa hways o Ang II
gene a ion [61 - 63] which a e impo an in physiological and pa hophysiological condi ions [64, 65]. Howe e , hese
pa hways a e no discussed u he in his e iew.
In 1940, Ang II an oc apep ide also known as Ang (1-8) was i s isola ed and cha ac e ized as a po en
asocons ic o ha aises BP and egula es e.g. elec oly e balance, ascula one and hi s [29, 30, 43]. I s imula es
he elease o aldos e one and asop essin and exe s i s ha m ul ac ions, such as asocons ic ion, ib osis and
in lamma ion ia G-p o ein coupled AT1R [42, 43, 66 - 68]. Fu he mo e, Ang II can also ac i a e angio ensin II ype 2
ecep o s (AT2R) whose ac i i ies a e hough o oppose hose o AT1R [31, 42, 43]. AT2Rs a e ega ded as p o ec i e
ecep o s as hey may elici asodila o y, an ihype ensi e, p oapop o ic as well as an ip oli e a i e e ec s [53, 69] and
as hey can bind di ec ly o AT1R hus inhibi ing signaling h ough i [31]. ACE inhibi o s a e used as an ihype ensi e
medica ions as hey oppose he ha m ul e ec s o Ang II ia AT1R by blocking he con e sa ion o Ang I o Ang II by
ACE1 hus ele a ing he le els o Ang(1-7) [42, 43].
Angio ensin II can hen be u he clea ed by ACE1 o aminopep idase A o gene a e angio ensin III (Ang III) o by
aminopep idase N o o m angio ensin IV (Ang IV) [20, 28, 42, 43]. Ang IV can also be gene a ed om Ang III by
aminopep idases N, M and B [28, 43]. Ang III exe s i s asocons ic i e ac ions ia he same ecep o s as Ang II
(highe a ini y o AT2R) whe eas Ang IV p e e s angio ensin II ype 4 ecep o s (AT4R) which a e ela ed o cogni i e
unc ions and p oli e a i e e ec s and which a e ound e.g. in b ain, lung and kidney [20, 70, 71]. Ang IV can also elici
i s biological e ec s, including enal asodila a ion, hype ophy and egula ion o cell g ow h, h ough ac i a ion o
AT1R [72].
Clea age o one amino acid esidue (Phe) om ca boxyl e minus o Ang I by ACE2 [73], ca boxypep idase A o
ca hepsin A [74, 75] gene a e angio ensin (1-9) (Ang(1-9)) whose main biological unc ions a e o elease a achidonic
acid, p omo e ni ic oxide o ma ion and inc ease b adykinin ac i i y [74]. Ang(1-9) may also educe BP, dec ease
hype ension [76] and possibly play a ole in inhibi ion o pla ele unc ion [77]. The o ma ion o Ang(1-9) is hough
o be dependen on ACE2 ac i i y [73, 78] and i has been sugges ed ha Ang(1-9) could media e i s ac ions by
ac i a ing he AT2 ecep o s [76, 79]. ACE2 (42% sequence iden i y o ACE1) was i s cloned in 2000 and has since
been iden i ied in mul iple o gans such as kidney, hea , b ain, li e and lung [42, 73, 80 - 82]. ACE2 has been shown o
con e Ang I o Ang(1-9) [73] and mos impo an ly o o m Ang(1-7) om Ang II [42, 80, 83 - 85]. This enzyme has
zinc me allopep idase consensus sequence (HEXXH) in i s ac i e si e and like i s homologue ACE2 ac i i y is also
egula ed by he p esence o chlo ide ions [42]. ACE2 clea es only one amino acid esidue om Ang II hus enhancing
Ang(1-7) o ma ion and lea ing less subs a e o ACE1 o ac on [42, 82]. Fu he mo e, ACE inhibi o s used as
an ihype ensi e medica ions do no block ACE2 ac i i y making his enzyme oge he wi h Ang(1-7) and MasR he
ocus o he esea ch ega ding RAS and ca dio ascula d ug de elopmen [80, 86].
Ang(1-7) ha was i s hough o be de oid o biological unc ion can be gene a ed om Ang II by ACE2, p olyl-
endopep idase and p olyl-ca boxypep idase [20, 43, 80, 87] o om Ang(1-9) by ACE1 and NEP [83]. I can also be
me abolized di ec ly om Ang I o om p oho mone Ang(1-12) bypassing he biosyn hesis o Ang II [43, 87].
Mo eo e , Ang(1-7) can be u he me abolized in o smalle pep ides such as angio ensin (1-5) o angio ensin (2-7)
[28].
RAS in he Eye The Open Oph halmology Jou nal, 2017, Volume 11 125
Ang(1-7) is known o ha e unc ions opposi e o hose o Ang II [43]. Al hough, Ang(1-7) may in e ac wi h AT1R
and AT2R [76, 79, 84, 86], his pep ide elici s i s asodila ing and an ip oli e a o y e ec s h ough ac i a ion o i s
main ecep o MasR [20, 42, 79, 84]. MasR is a G-p o ein coupled ecep o [88] ha was i s desc ibed as a p o o-
oncogene [89]. This ecep o has been ound e.g. in eye, cen al ne ous sys em, kidney, hea and b ain [88, 90 - 93]
and is known o ac an agonis ically o AT1R [53]. Due o i s an ia hy hmogenic, an i h ombogenic, g ow h-inhibi o y
and asocons ic i e inhibi o y p ope ies, Ang(1-7) is seen as a p o ec i e pep ide ha ac s as a coun e egula o wi hin
RAS [38 - 40]. In e es ingly, he associa ion be ween Ang(1-7) and pa hology o mul iple diseases such as hype ension
[84, 86, 87, 94 - 98] and diabe ic neph opa hy [46, 99, 100] makes his pep ide a po en ial a ge o d ug de elopmen .
In e es ingly, in addi ion o ACE2-Ang(1-7)-MasR axis, a newly desc ibed membe o RAS, angio ensin(3-4)
(Ang(3-4)) coun e ac s he adi ional ACE1-Ang II-AT1R pa hway bo h sys emically and locally[101]. Ang(3-4) has
an ihype ensi e e ec s ha a e media ed ia AT2 ecep o s. This dipep ide is an ip oli e a i e and asodila ing and i
inhibi s ACE1. Fu he mo e, i is e ec i e when adminis e ed o ally, as i pe mea es in es inal cells ela i ely easily,
lowe s Ang II and aldos e one le els in plasma and inhibi s ACE1. Ang(3-4) le els a e highe in heal hy indi iduals
han in hype ensi e pa ien s [101]. All in all, i emains open wha a e he he apeu ic possibili ies o Ang(3-4) and i s
po en ial unc ions in local RA-sys ems beyond enal issue such as in eye.
In addi ion o p e iously men ioned angio ensin pep ides and enzymes, he e a e se e al di e en pep idases,
p o eases and small pep ides ha a e pa o he RAS cascade bu a e no discussed in his e iew. Howe e , all o hese
enzymes and smalle angio ensin pep ides a e shown in Fig. (1). In addi ion, he kallik ein-kinin sys em ha is also
shown in Figu e 1 and ha in e ac s wi h RAS is no discussed in de ail in his e iew.
TISSUE RAS
E en hough ci cula o y RAS has many impo an oles in human body, a ious o gans ha e hei own issue
speci ic RA-sys ems ha elici long e m changes and local e ec s such as g ow h, p oli e a ion and p o ein syn hesis a
o gan le el [20, 31, 64]. Gan en e al. 1971 we e he i s esea che s o show ha RAS is also an o gan speci ic sys em
ha has impo an egula o y oles a issue le el [102]. Fo example, hea , b ain, in es ine and e en he human eye
ha e hei own local RA-sys ems [6, 31, 43].
La e , local RA-sys ems we e di ided in o wo g oups based on he o igin o Ang II: ex insic RAS ge s i s Ang II
om he ci cula ion whe eas in insic RAS syn hesises i s own Ang II locally [103]. Al hough some o he local RA-
sys ems depend on in e ac ions wi h ci cula o y RAS o ully ope a e, in many o gans issue RA-sys ems p e e o
unc ion independen ly [43]. Indeed local issue-speci ic RA-sys ems can independen ly p oduce di e en componen s
o RAS hus p o ing ha RAS is mo e han jus an endoc ine ci cula o y sys em and ha i egula es mo e unc ions
han sugges ed ea lie [6, 31, 43, 64].
Local ocula RAS has been ound pa ly in he eye. So a all o he cen al componen s o RAS including he
componen s o he wo main axes: ACE1-Ang II-AT1R and ACE2-Ang(1-7)-MasR ha e been iden i ied in di e en eye
s uc u es in a ious species [6, 9]. In he human eye, elemen s o he wo main axes ha e been iden i ied in e inal as
well as in non- e inal ocula s uc u es [6, 93, 104]. Tables (1 and 2) summa ize he localiza ion o RAS pep ides,
enzymes and ecep o s in non- e inal ocula s uc u es o he human eye.
Table 1. Renin-angio ensin sys em componen s in bulba conjunc i a, co nea, abecula meshwo k, aqueous humo , i is,
cilia y body and non-pigmen ed cilia y epi helium, o he human eye.
RAS componen Bulba conjunc i a Co nea T abecula
meshwo k Aqueous humo I is Cilia y body/NPE Re e ences
P o enin x x x x x [24, 105 - 108]
Renin x x x x [105, 108]
AGT x x x x x [105, 109, 110]
ACE1 x x x x x x [104, 105, 110 - 116]
ACE2 x [104]
Ang I x x x [117, 118]
Ang II x x x x x x [111, 117 - 119]
Ang(1–7) x x x [93, 104]
(P)RR x x x x [105]
126 The Open Oph halmology Jou nal, 2017, Volume 11 Holappa e al.
RAS componen Bulba conjunc i a Co nea T abecula
meshwo k Aqueous humo I is Cilia y body/NPE Re e ences
AT, unknown sub ype x x [120, 121]
AT1R x x x x [105, 119, 122]
AT2R x x [119]
AT4R
MasR x x x [93]
Table modi ied and upda ed om he able published by Holappa e al. [123]. ACE1, -2: Angio ensin con e ing enzyme 1, -2; AGT:
Angio ensinogen; Ang I, -II: Angio ensin I, -II; Ang(1–7): Angio ensin (1–7); AT1R, -2R, -4R: Angio ensin II ype 1, 2, 4 ecep o ; MasR: Mas
ecep o ; NPE: Non-pigmen ed cilia y epi helium; (P)RR: (p o) enin ecep o ; RAS: Renin-angio ensin sys em.
Table 2. Renin-angio ensin sys em componen s in lens, ea s and lac imal gland, i eous, op ic ne e head and scle a o he
human eye.
RAS componen Lens Tea s/Lac imal gland Vi eous Op ic ne e head Scle a Re e ences
P o enin x x [24, 105, 107]
Renin x x [24, 105]
AGT x x [105, 110]
ACE1 x x x x [105, 112, 114, 115, 124 - 127]
ACE2
Ang I x [117]
Ang II x x [111, 119]
Ang(1–7)
(P)RR x [105]
AT, unknown sub ype
AT1R x [119]
AT2R x [119]
AT4R
MasR
Table modi ied and upda ed om he able published by Holappa e al. [123]. ACE1, -2: Angio ensin con e ing enzyme 1, -2; AGT:
Angio ensinogen; Ang I, -II: Angio ensin I, -II; Ang(1–7): Angio ensin (1–7); AT1R, -2R, -4R: Angio ensin II ype 1, 2, 4 ecep o ; MasR: Mas
ecep o ; (P)RR: (p o) enin ecep o ; RAS: Renin-angio ensin sys em.
E en hough RAS is p esen in he human eye, i s unc ion and signi icance in ocula pa hophysiology is s ill
unknown. Whe he angio ensin pep ides ound in he human eye o igina e pa ially om he blood compa men o a e
syn hesized locally has been he opic o he deba e [117]. Ci cula ing angio ensins e.g. Ang I and Ang II canno pass
he blood-b ain ba ie and canno each he i eous luid when blood- e ina ba ie in he eye is in ac [24, 117, 128,
129]. Mo eo e , in po cine eyes Ang I and Ang II le els a e shown o be 5 o 100- old highe han hose ound om
di usion o blood [117] and in compa ison o plasma ACE1 ac i i y a e highe in ocula s uc u es o pig and abbi
eyes [130, 131]. Howe e , in aocula RAS may play a ole in he egula ion o IOP h ough i s e ec s on AH dynamics
[9, 31]. Ang II has been sugges ed o inc ease AH sec e ion ia AT1R [122]. Animal s udies as well as s udies on
di e en pa ien g oups indica e ha sys emic an ihype ensi e RAS-inhibi ing medica ions such as ACE inhibi o s
[103, 132, 133], ARBs [134 - 136] and enin inhibi o s [137], educe IOP. Mo eo e , in aocula RAS and i s ac ions
ha e been linked o a ious eye diseases [6, 138].
EYE DISEASES AND LOCAL RAS
Glaucoma
Glaucoma is a mul i ac o ial long- e m neu odegene a i e diso de which can be cha ac e ized by he non-apop o ic
and apop o ic dea h o e inal ganglion cells and he loss o e inal ne e ibe s all o which lead o loss o isual ield
[6, 7, 9, 10]. The dea h o e inal ganglion cells leads o inc eased IOP which is he mos impo an isk ac o o he
de elopmen o glaucoma and he only isk ac o amenable o ea men [15, 138, 139]. Inc eased IOP can lead o
ischemia, mechanical impai men , oxida i e s ess and op ic ne e in lamma ion [140]. Howe e , no e e y pa ien wi h
high IOP de elops glaucoma no do all he glaucoma pa ien s ha e inc eased IOP [15]. Se e al o he isk ac o s such
as age, amily his o y, diabe es, ascula dys unc ion and sys emic hype ension ha e also been linked o glaucoma [6, 9
(Table 1) con d.....

RAS in he Eye The Open Oph halmology Jou nal, 2017, Volume 11 127
- 11, 139, 141 - 144]. In addi ion o gene ic and en i onmen al ac o s, epigene ics also a ec he signaling pa hways
ha a e held esponsible o glaucoma p og ession [145, 146].
IOP is main ained by a homeos a ic balance be ween o ma ion and ou low o AH. In he heal hy human eye, he
low o AH agains esis ance gene a es an IOP o abou 15 mmHg ( ange 9-21 mmHg) [147 - 149]. Diu nal a ia ion
o IOP is abou 5 mmHg in heal hy subjec s. Highe IOP alues a e no mally measu ed in he mo ning. T ansien
pos u al IOP a ia ions can be e en wo old e.g. in yoga p ac ione s du ing si sasana, heads and pos u e [150]. In
addi ion, physical exe cise can in luence ocula p essu e [151, 152]. Typically ae obic exe cise educes IOP due o he
be e ocula ci cula ion [153] whe eas anae obic exe cise ele a es IOP due o he ansien obs uc ed ocula ci cula ion
[154]. The p essu e is needed o main ain he op ical and e ac i e p ope ies o he eye [148, 149, 155]. One o he
o he undamen al unc ions o IOP is o main ain he igh shape o he eye [148, 155]. The no mal AH o ma ion a e
(2.5-2.8µL/min) is lowe while sleeping (1.5µL/min) and can be educed wi h ageing and in some sys emic diseases
such as in diabe es [9, 139, 156].
AH is a mix u e o di e en elec oly es, g ow h ac o s, p o eins, amino acids, cy okines, ino ganic and o ganic
solu es [157 - 161]. Ci cula ing AH no only sus ains and nou ishes non- ascula ized eye s uc u es e.g. co nea and lens
bu i also emo es exc e o y p oduc s, anspo s neu o ansmi e s and enables media o s and in lamma o y cells o
ci cula e in he eye [9, 156]. Cilia y body epi helial is he si e o AH p oduc ion [147]. Al hough wo passi e p ocesses:
di usion and ul a il a ion, ha equi e no cellula ac i i y no ene gy [148], also pa icipa e on AH p oduc ion [162],
ac i e sec e ion accoun s o 80-90% o he o al AH o ma ion [155, 156, 163]. Ac i e and selec i e ans-cellula
anspo o ions and molecules ac oss he epi helium agains concen a ion g adien equi es ene gy ha is gene a ed by
hyd olysis o adenosine iphospha e (ATP) by Na+/K+ ATPase. Na+ and K+ ac i a e ATP hyd olysis whe eas di e en
molecules such as dini ophenol and anada e inhibi Na+/K+ ATPase [156, 164, 165]. Mo eo e , ac i e anspo o Na+
in o he pos e io chambe causes wa e low om he s omal pool in o he pos e io chambe and wo aquapo ins
(AQP1 and AQP4) ha e been shown o con ibu e o AH o ma ion [166, 167]. O he ions and molecules ha a e
ac i ely anspo ed ac oss he epi helium include Cl-, HCO3-, asco bic acid and ce ain amino acids. Howe e , ac i e
anspo o hese componen s occu o a lesse ex en [156, 166, 168 - 170]. A e he p oduc ion and sec e ion in o he
pos e io chambe , AH lows be ween he lens and he i is in o he an e io chambe om whe e i will be disposed
[157, 171, 172].
F om he an e io chambe , AH lows h ough he abecula meshwo k and he canal o Schlemm in o he enous
blood sys em [147]. AH can exi he eye h ough he abecula , he u eoscle al o he u eolympha ic pa hways [139]
om which he i s is p essu e-dependen main ou e o d ainage accoun ing o 90% o all AH ou low [9, 139, 173].
Aqueous humo lows h ough he po ous abecula meshwo k passi ely when app op ia e IOP le el is eached and
AH ge s il e ed in he p ocess [174]. The ac in cy oskele on and he adhesions o abecula meshwo k cells a ec he
luid ou low h ough he abecula meshwo k [175]. The i s ou e o d ainage can also be desc ibed as he
con en ional pa hway [176] which a e limi ing s ep is he low h ough he inne wall o Schelmm's canal [58]. F om
Schelmm's canal dozens o collec o channels connec wi h aqueous eins h ough which AH lows in o he ci cula o y
sys em [177, 178].
In addi ion o abecula pa hway some AH exi he eye h ough he u eosscle al ou e [179]. In compa ison o he
abecula pa hway he u eoscle al pa hway is ela i ely independen o IOP and unde goes age-dependen changes
[173, 179]. The u eoscle al ou e o d ainage can also be desc ibed as he uncon en ional pa hway in which AH d ains
h ough he cilia y muscle and exi s h ough he sup acilia y space ac oss he an e io /pos e io scle a in o he cho oidal
essels and e u ns o sys emic ci cula ion [180, 181]. The a e limi ing s ep in u eoscle al pa hway is he low h ough
he cilia y muscle [179].
The hi d ou e o d ainage ha is hough o wo k as a backup sys em is loca ed in channels o he cilia y body
s oma and in es inal space be ween cilia y muscle bundles [182]. O he mino ou low pa hways ia i is essels,
co neal endo helium and an e io i eous body ha e also been desc ibed [183]. As IOP is he ne sum o aqueous
humo o ma ion and ou low, an i-glaucoma ous ea men s aim o lowe IOP by ei he dec easing he a e o AH
o ma ion o by inc easing AH d ainage [184]. Lowe ing IOP by lase he apy, ocula hypo ensi e medica ions o
su gical p ocedu es is cu en ly he only he apeu ic ool o ea his de as a ing disease [6, 9, 10, 28].
Some s udies ha e sugges ed ha d ugs a ec ing RAS by blocking i s ac ion e.g. ACE inhibi o s [132, 133, 185]
and ARBs [134, 135] migh be po en ial an i-glaucoma ous d ugs in he u u e. Animal s udies also suppo hese
indings [103, 133, 135 - 137]. ACE inhibi o s can a ec IOP le els h ough hei ac ions on AH dynamics. These
128 The Open Oph halmology Jou nal, 2017, Volume 11 Holappa e al.
inhibi o s can dec ease Ang II le els in AH, hus a ec ing he u eoscle al ou low [118, 186, 187], and slow down AH
o ma ion by lowe ing blood low in he cilia y body [188] which is he p ima y si e o AH p oduc ion. ACE inhibi o s
also ac h ough kallik ein-kinin sys em. By blocking he b eakdown o b adykinin hese inhibi o s suppo
p os aglandin syn hesis which in u n lowe s IOP by ele a ing u eoscle al ou low [189 - 191]. By p e en ing
b adykinin b eakdown ACE inhibi o s also cause asodila a ion as hei ac ions lead o inc eased ni ic oxide o ma ion
by endo helial cells. Bo h p os aglandins and ni ic oxide being asodila o y also inhibi he syn hesis o
asocons ic i e pep ide endo helin-1 [192 - 195]. In addi ion, ARBs ha e been sugges ed o ele a e u eoscle al
ou low and slow down cell dea h o e inal ganglion cells [195, 196].
RAS componen s ha e also been iden i ied in cen al s uc u es o he eye esponsible o AH o ma ion and RAS
ac i i y has been epo ed in cul u ed human non-pigmen ed cilia y epi helial cells [6, 120, 122]. In e es ingly, Ang(1-7)
ha ac s ia MasR and ACE2 ac i a ing diminazene ace u a e (DIZE) ha e been epo ed o ha e posi i e e ec s on
glaucoma by dec easing IOP [41, 197, 198]. Indeed, as Ang(1-7) ac ions a e opposi e o hose o Ang II, his
hep apep ide is hough o ha e bene icial e ec s on he human body including he eye. Mo eo e , ACE2 ac i a ing
compounds a e conside ed as no el pha maco he apeu ic agen s [7, 41, 199 - 201].
Whe eas Ang(1-7) and ACE2 ac i a ion a e hough o ha e posi i e e ec s on IOP, Ang II has sugges ed o ha e
nega i e e ec s on he human eye e en hough some o he esul s a e con o e sy. Ang II augmen s cell p oli e a ion
in abecula meshwo k and inc eases collagen syn hesis in i o [187]. In acame ally adminis e ed Ang II also lowe s
u eoscle al ou low [41] whe eas in ca s in a enously adminis e ed Ang II dec eases IOP [202]. Ang II can also ac as
a sec e agogue pep ide in non-pigmen ed cilia y cells [122] as i p omo es po assium ion channel ac i i y h ough Ca2+
signaling [203] and causes highe cy oplasmic sodium concen a ion by ac i a ing Na+/H+ exchange [163]. Imbalances
in sodium handling in cilia y and enal ubula epi helium migh explain he associa ion be ween glaucoma and
hype ension [204]. On he o he hand, de ec s in au o egula ion o he pos e io cilia y ci cula ion [205] and
mic o ascula damage a ec ing he op ic ne e blood supply [206] bo h caused by hype ension could also explain he
coexis ence o hype ension and glaucoma. Fu he mo e, hypo ensi e pe iods caused by an ihype ensi e medica ions
can also lead o inju ed op ic ne e ibe s [207].
Diabe ic Re inopa hy
Diabe ic e inopa hy (DR) is one o he mos leading causes o blindness wo ldwide and one o he mos common
mic o ascula complica ions o diabe es [208 - 210]. As diabe es becomes mo e and mo e common among adul s, he
incidences o DR a e p edic ed o ise d ama ically. Nea ly all pa ien s wi h ype 1 diabe es and almos 60% o pa ien s
su e ing om ype 2 diabe es show some signs o DR la e in diabe es [211]. Many ac o s such as high BP,
hype glycemia, hype lipidemia, age and oxida i e s ess play a ole in he de elopmen o DR [212, 213]. The ea ly
s a e o he disease is desc ibed as non-p oli e a i e DR (NPDR) in which mic oaneu ysms a e o med due o he
weakened e inal blood essels and blood- e inal ba ie b eaks down. A e he o ma ion o mic oaneu ysms, luid can
leak in o e ina causing swelling o he macula. P oli e a i e DR (PDR) is used o mo e se ious and ad anced o m o
DR. In addi ion o he symp oms seen in NPDR, PDR also mani es s blood essel g ow h on he su ace o he e ina
and in o he i eous [209, 214, 215].
S udies ha e shown ha RAS, especially Ang II media ed ac ions h ough AT1R, is in ol ed in he p og ession o
DR [31, 52, 94, 216 - 218]. O e -exp ession o Ang II and p o enin as well as ascula endo helial g ow h ac o
(VEGF) exis s in i eous humo o indi iduals su e ing om DR [24, 219 - 221]. Ang II p omo es angiogenesis and
possibly inc eases he isk o neo ascula iza ion and hype pe meabili y by inc easing he e inal blood essel
pe meabili y [219, 220, 222 - 225]. Fu he mo e, (P)RR has been linked o he de elopmen o DR h ough i s di ec
e ec s on exp ession o angiogenic molecules in e inal cells [226 - 229]. RAS in ol emen in angiogenesis has
p omo ed esea ch concen a ing on he po en ial he apeu ic ole o RAS inhibi o s in DR [230]. Blocking he RAS
cascade can ac ually slow down he p og ession o he disease [231 - 233] especially in no mo ensi e pa ien s [234]. In
pa ien s wi h ype 1 and ype 2 diabe es, a link be ween dec eased blood p essu e and educed DR p og ession has been
desc ibed [235, 236]. RAS inhibi o s can educe he isk o DR and possibly a ec he p og ession o he disease in
diabe ic pa ien s [229]. In addi ion, ACE2 ac i a ion educes e inal ganglion cell dea h in hype glycemic a s [198].
A e all, mo e basic esea ch and andomized clinical ials a e needed in he u u e o esol e he exac mechanism o
ac ion o RAS compounds.
RAS in he Eye The Open Oph halmology Jou nal, 2017, Volume 11 129
Age- ela ed Macula Degene a ion
Age- ela ed macula degene a ion (AMD) is a majo cause o i e e sible ision loss among aged popula ion. This
de as a ing disease is he eason why 8.7% o people wo ldwide su e om blindness [237]. Whe eas d y AMD is
cha ac e ized wi h he signi ican loss o pho o ecep o s leading o he loss o cen al ision, we o m o AMD causes
cho oidal neo ascula iza ion in which pa hologically g own blood essels pene a e B uch's memb ane and popula e
e ina. 90% o AMD cases a e diagnosed as d y o m o AMD. In e es ingly, in addi ion o many isk ac o s such as
old age, smoking, sys emic hype ension as well as en i onmen al and gene ic ac o s imbalances in RAS cascade ha e
also been connec ed o he de elopmen o AMD [6, 22, 208, 238 - 241].
Ci cula ing RAS is known o i s ole as he egula o o BP and de ec s in RAS cascade can lead o sys emic
hype ension which in u n aises he isk o de eloping AMD. Fu he mo e, Ang II modula es e inal pigmen
epi helium which sugges s ha impai men in RAS egula ion migh a ec he unc ion o e inal pigmen epi helium as
well as he iabili y o pho o ecep o s. Ang II a ec s e inal angiogenesis which in u n sugges s ha his
asocons ic i e oc apep ide migh also be in ol ed in cho oidal neo ascula isa ion [6, 238]. The ac i a ion o wo
ypes o RAS ecep o s: AT1R and (P)RR ha e also been linked o he de elopmen o AMD [242, 243]. Animal
s udies ha e shown ha losa an an AT1R an agonis [244], ARBs [245], ACE inhibi o s [239] and (P)RR inhibi o s
[243] ha e posi i e e ec s on AMD as hese compounds can educe cho oidal neo ascula iza ion by supp essing
in lamma o y agen s. As o oday, no e ec i e he apies a e a ailable o ea men o d y AMD [246]. Howe e ,
unde s anding he ole o RAS in he de elopmen o AMD migh help us manage and slow down he p og ession o
his disease [138, 247].
Re inopa hy o P ema u i y
Whe eas AMD a ec s elde ly people, e inopa hy o p ema u i y (ROP) is an eye disease ha only a ec s
p ema u e newbo ns (bo n <32 weeks) and can lead o pe manen ision loss [25, 238]. The main isk ac o s iden i ied
o de elopmen o ROP a e lowe ges a ional age and low bi h weigh (<1.5 kg). In indus ialized coun ies, oughly
wo- hi ds o newbo ns wi h bi h weigh less han 1.25 kg mani es some signs o ROP. All he isk ac o s iden i ied
o his disease co ela e wi h e inal imma u i y a bi h [25, 248]. ROP can be cha ac e ized as neo ascula disease in
which e inal neo ascula isa ion leads o se e al complica ions such as macula d agging, ac ional e inal de achmen
and i al haemo hage [238]. When a p ema u e newbo n is b ough in o a high oxygen en i onmen , he g ow h o
e inal blood essels ha expand om he op ic ne e hal s. A e oxygen condi ions a e no malized, he inne e inal
ascula u e ails o egain he no mal g ow h which in u n c ea es an a ascula a ea and leads o neo ascula isa ion,
epi e inal angiogenesis and possibly loss o ision ield [249]. Today, lase pho ocoagula ion and in a i eal injec ions
o be acizumab o pegap anib a e used as he apeu ic ools o manage ROP [25, 250, 251].
In e es ingly, s udies ha e shown ha newbo ns ha a e su e ing om ROP ha e had inc eased le els o se um
p o enin [252], ocula enin [253, 254] as well as inc eased AT1R and AT2R exp ession [253]. Mo eo e , s udies using
animal models wi h oxygen induced e inopa hy ha e shown ha ACE inhibi o s and AT1R an agonis ea men s
du ing he no mal ai condi ions can educe pa hological angiogenesis in e ina [253, 255 - 257]. Howe e , he e ec s
o ea ing e inal angiogenesis wi h AT2R an agonis and he possible ole o AT2R in e inal ascula pa hology a e
s ill unce ain [223, 254, 256, 258]. Na h e al. s udied RAS in ol emen in ROP in in an pa ien s (n=44) su e ing
om ROP as well as in a s wi h oxygen induced e inopa hy. They ound signi ican ly highe le els o AGT, ACE1
and Ang II, in i eous humo o in an s su e ing om ROP compa ed o heal hy con ols. Renin le els we e also
inc eased bu he di e ence was ound o be s a is ically no signi ican . In animal s udies up- egula ed mRNA
exp essions o enin, AGT, ACE1 and AT1R we e ound in e ina o he a s su e ing om oxygen induced
e inopa hy. Fu he mo e, ACE inhibi o (lisinop il) and ARB ( elmisa an) we e shown o supp ess he o e -ac i a ion
induced ascula and e inal unc ional changes in ROP [25]. Howe e , u he esea ch is needed o unde s and he
in ol emen o RAS in he de elopmen and ea men o ROP.
CONCLUSION
In e es ingly, in addi ion o ci cula ing RAS ha is in ol ed in BP egula ion and in lamma ion, local issue speci ic
RAS has been iden i ied in many o gans o he human body including he eye. I has been de ec ed in a ious pa s o
he eye e en in he s uc u es in ol ed in aqueous humo o ma ion and ou low. These in iguing obse a ions should
p omo e mo e esea ch concen a ing on he possible ole o local RAS in aqueous humo dynamics and hus IOP
egula ion. Howe e , ac o s such as e inal ganglion cell dea h due o o he easons han p essu e migh also be
130 The Open Oph halmology Jou nal, 2017, Volume 11 Holappa e al.
in ol ed in glaucoma p og ession. Iden i ica ion o he second coun e - egula ing axis o RAS (ACE2-Ang(1-7)-MasR)
has al eady b ough new oppo uni ies in o ligh , and compounds a ec ing Ang(1-7) syn hesis as well as MasR and
ACE2 ac i i y o e new and exci ing possibili ies o ocula pha macology in he u u e.
CONSENT FOR PUBLICATION
No applicable.
CONFLICT OF INTEREST
The au ho con i ms ha his a icle con en has no con lic o in e es .
ACKNOWLEDGEMENTS
Glaukooma ukisää iö Lux (AV) and Finska Läka esällskape Eina och Ka in S oems S i else (HV). Au ho
con ibu ions: MH collec ed he li e a u e, p epa ed he ables and he igu e and w o e he p elimina y e sion o he
e iew a icle; HV e ised he ex ; and AV e ised he ex and submi ed he a icle.
REFERENCES
[1] Quigley HA, B oman AT. The numbe o people wi h glaucoma wo ldwide in 2010 and 2020. B J Oph halmol 2006; 90(3): 262-7.
[h p://dx.doi.o g/10.1136/bjo.2005.081224] [PMID: 16488940]
[2] Lei e MT, Saka a LM, Medei os FA. Managing glaucoma in de eloping coun ies. A q B as O almol 2011; 74(2): 83-4.
[h p://dx.doi.o g/10.1590/S0004-27492011000200001] [PMID: 21779659]
[3] Ro ch o d AP, Ki wan JF, Mulle MA, Johnson GJ, Roux P. Temba glaucoma s udy: a popula ion-based c oss-sec ional su ey in u ban
Sou h A ica. Oph halmology 2003; 110(2): 376-82.
[h p://dx.doi.o g/10.1016/S0161-6420(02)01568-3] [PMID: 12578784]
[4] F iedman DS, Wol s RC, O’Colmain BJ, e al. P e alence o open-angle glaucoma among adul s in he Uni ed S a es. A ch Oph halmol 2004;
122(4): 532-8.
[h p://dx.doi.o g/10.1001/a choph .122.4.532] [PMID: 15078671]
[5] Day AC, Baio G, Gazza d G, e al. The p e alence o p ima y angle closu e glaucoma in Eu opean de i ed popula ions: a sys ema ic e iew.
B J Oph halmol 2012; 96(9): 1162-7.
[h p://dx.doi.o g/10.1136/bjoph halmol-2011-301189] [PMID: 22653314]
[6] Giese MJ, Spe h RC. The ocula enin-angio ensin sys em: a he apeu ic a ge o he ea men o ocula disease. Pha macol The 2014;
142(1): 11-32.
[h p://dx.doi.o g/10.1016/j.pha m he a.2013.11.002] [PMID: 24287313]
[7] Fou eaux G, Noguei a JC, Noguei a BS, e al. An iglaucoma ous e ec s o he ac i a ion o in insic Angio ensin-con e ing enzyme 2.
In es Oph halmol Vis Sci 2013; 54(6): 4296-306.
[h p://dx.doi.o g/10.1167/io s.12-11427] [PMID: 23702784]
[8] Liu T, Xie L, Ye J, Liu Y, He X. Sc eening o candida e genes o p ima y open angle glaucoma. Mol Vis 2012; 18: 2119-26.
[PMID: 22876139]
[9] Vaajanen A, Vapaa alo H. Local ocula enin-angio ensin sys em - a a ge o glaucoma he apy? Basic Clin Pha macol Toxicol 2011;
109(4): 217-24.
[h p://dx.doi.o g/10.1111/j.1742-7843.2011.00729.x] [PMID: 21599836]
[10] Wein eb RN, Khaw PT. P ima y open-angle glaucoma. Lance 2004; 363(9422): 1711-20.
[h p://dx.doi.o g/10.1016/S0140-6736(04)16257-0] [PMID: 15158634]
[11] Tuulonen A, Fo sman E, Hagman J, e al. [Upda e on Cu en Ca e Guideline: Glaucoma]. Duodecim 2015; 131(4): 356-8.
[PMID: 26241991]
[12] Cap ioli J, Coleman AL. In aocula p essu e luc ua ion a isk ac o o isual ield p og ession a low in aocula p essu es in he ad anced
glaucoma in e en ion s udy. Oph halmology 2008; 115(7): 1123-1129.e3.
[h p://dx.doi.o g/10.1016/j.oph ha.2007.10.031] [PMID: 18082889]
[13] Ke sey T, Clemen CI, Bloom P, Co dei o MF. New ends in glaucoma isk, diagnosis & managemen . Indian J Med Res 2013; 137(4):
659-68.
[PMID: 23703333]
[14] Wein eb RN, Aung T, Medei os FA. The pa hophysiology and ea men o glaucoma: a e iew. JAMA 2014; 311(18): 1901-11.
[h p://dx.doi.o g/10.1001/jama.2014.3192] [PMID: 24825645]
[15] Schmidl D, Schme e e L, Ga hö e G, Popa-Che echeanu A. Pha maco he apy o glaucoma. J Ocul Pha macol The 2015; 31(2): 63-77.
[h p://dx.doi.o g/10.1089/jop.2014.0067] [PMID: 25587905]
RAS in he Eye The Open Oph halmology Jou nal, 2017, Volume 11 137
[140] Gau hie AC, Liu J. Neu odegene a ion and neu op o ec ion in glaucoma. Yale J Biol Med 2016; 89(1): 73-9.
[PMID: 27505018]
[141] Khawaja AP, Chan MP, B oadway DC, e al. Sys emic medica ion and in aocula p essu e in a B i ish popula ion: he EPIC-No olk Eye
S udy. Oph halmology 2014; 121(8): 1501-7.
[h p://dx.doi.o g/10.1016/j.oph ha.2014.02.009] [PMID: 24702754]
[142] McGwin G J , McNeal S, Owsley C, Gi kin C, Eps ein D, Lee PP. S a ins and o he choles e ol-lowe ing medica ions and he p esence o
glaucoma. A ch Oph halmol 2004; 122(6): 822-6.
[h p://dx.doi.o g/10.1001/a choph .122.6.822] [PMID: 15197056]
[143] Budenz DL. A clinician’s guide o he assessmen and managemen o nonadhe ence in glaucoma. Oph halmology 2009; 116(11)(Suppl.):
S43-7.
[h p://dx.doi.o g/10.1016/j.oph ha.2009.06.022] [PMID: 19837260]
[144] Schwa z GF, Quigley HA. Adhe ence and pe sis ence wi h glaucoma he apy. Su Oph halmol 2008; 53(Suppl. 1): S57-68.
[h p://dx.doi.o g/10.1016/j.su oph hal.2008.08.002] [PMID: 19038625]
[145] Gau hie AC, Liu J. Epigene ics and Signaling Pa hways in Glaucoma. Biomed. Res. In . A ailable om: h ps://www.hindawi.com/jou nals/
bm i/2017/5712341/. 2017. 2017: 5712341
[h p://dx.doi.o g/10.1155/2017/5712341]
[146] Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global p e alence o glaucoma and p ojec ions o glaucoma bu den h ough
2040: a sys ema ic e iew and me a-analysis. Oph halmology 2014; 121(11): 2081-90.
[h p://dx.doi.o g/10.1016/j.oph ha.2014.05.013] [PMID: 24974815]
[147] Janssen SF, Go gels TG, an de Spek PJ, Jansonius NM, Be gen AA. In silico analysis o he molecula machine y unde lying aqueous
humo p oduc ion: po en ial implica ions o glaucoma. J Clin Bioin o ma 2013; 3(1): 21.
[h p://dx.doi.o g/10.1186/2043-9113-3-21] [PMID: 24165276]
[148] Ci an MM, Macknigh AD. The ins and ou s o aqueous humou sec e ion. Exp Eye Res 2004; 78(3): 625-31.
[h p://dx.doi.o g/10.1016/j.exe .2003.09.021] [PMID: 15106942]
[149] B ubake RF. The low o aqueous humo in he human eye. T ans Am Oph halmol Soc 1982; 80: 391-474.
[PMID: 6763801]
[150] Baska an M, Raman K, Ramani KK, Roy J, Vijaya L, Bad ina h SS. In aocula p essu e changes and ocula biome y du ing Si sasana
(heads and pos u e) in yoga p ac i ione s. Oph halmology 2006; 113(8): 1327-32.
[h p://dx.doi.o g/10.1016/j.oph ha.2006.02.063] [PMID: 16806478]
[151] Dane S, Koçe I, Demi el H, Uçok K, Tan U. Long- e m e ec s o mild exe cise on in aocula p essu e in a hle es and seden a y subjec s. In
J Neu osci 2006; 116(10): 1207-14.
[h p://dx.doi.o g/10.1080/00207450500516461] [PMID: 16923688]
[152] Dane S, Koçe I, Demi el H, Ucok K, Tan U. E ec o acu e submaximal exe cise on in aocula p essu e in a hle es and seden a y subjec s.
In J Neu osci 2006; 116(10): 1223-30.
[h p://dx.doi.o g/10.1080/00207450500522501] [PMID: 16923690]
[153] Ma cus DF, K upin T, Podos SM, Becke B. The e ec o exe cise on in aocula p essu e. I. Human beings. In es Oph halmol 1970; 9(10):
749-52.
[PMID: 5479444]
[154] Viei a GM, Oli ei a HB, de And ade DT, Bo a o M, Ri ch R. In aocula p essu e a ia ion du ing weigh li ing. A ch Oph halmol 2006;
124(9): 1251-4.
[h p://dx.doi.o g/10.1001/a choph .124.9.1251] [PMID: 16966619]
[155] Ma k HH. Aqueous humo dynamics in his o ical pe spec i e. Su Oph halmol 2010; 55(1): 89-100.
[h p://dx.doi.o g/10.1016/j.su oph hal.2009.06.005] [PMID: 19783023]
[156] Goel M, Picciani RG, Lee RK, Bha acha ya SK. Aqueous humo dynamics: a e iew. Open Oph halmol J 2010; 4: 52-9.
[h p://dx.doi.o g/10.2174/1874364101004010052] [PMID: 21293732]
[157] To CH, Kong CW, Chan CY, Shahidullah M, Do CW. The mechanism o aqueous humou o ma ion. Clin Exp Op om 2002; 85(6): 335-49.
[h p://dx.doi.o g/10.1111/j.1444-0938.2002. b02384.x] [PMID: 12452784]
[158] F eddo TF. The Glenn A. F y Awa d Lec u e 1992: aqueous humo p o eins: a key o unlocking glaucoma? Op om Vis Sci 1993; 70(4):
263-70.
[h p://dx.doi.o g/10.1097/00006324-199304000-00003] [PMID: 8502454]
[159] McLa en JW, Ziai N, B ubake RF. A simple h ee-compa men model o an e io segmen kine ics. Exp Eye Res 1993; 56(3): 355-66.
[h p://dx.doi.o g/10.1006/exe .1993.1046] [PMID: 8472791]
[160] Ba so i MF, Ba els SP, F eddo TF, Kamm RD. The sou ce o p o ein in he aqueous humo o he no mal monkey eye. In es Oph halmol
Vis Sci 1992; 33(3): 581-95.
[PMID: 1544784]
[161] F eddo TF, Ba els SP, Ba so i MF, Kamm RD. The sou ce o p o eins in he aqueous humo o he no mal abbi . In es Oph halmol Vis Sci

138 The Open Oph halmology Jou nal, 2017, Volume 11 Holappa e al.
1990; 31(1): 125-37.
[PMID: 2298533]
[162] Milla J, T ue Gable B, Kau man P. Aqueous humo dynamics. A e iew. Open Op ho J 2010; 4: 52-9.
[163] Hou Y, Delame e NA. In luence o ANG II on cy oplasmic sodium in cul u ed abbi nonpigmen ed cilia y epi helium. Am J Physiol Cell
Physiol 2002; 283(2): C552-9.
[h p://dx.doi.o g/10.1152/ajpcell.00459.2001] [PMID: 12107065]
[164] Cousins SW, McCabe MM, Danielpou D, S eilein JW. Iden i ica ion o ans o ming g ow h ac o -be a as an immunosupp essi e ac o in
aqueous humo . In es Oph halmol Vis Sci 1991; 32(8): 2201-11.
[PMID: 2071334]
[165] Becke B. Vanada e and aqueous humo dynamics. P oc o Lec u e. In es Oph halmol Vis Sci 1980; 19(10): 1156-65.
[PMID: 6106642]
[166] Cap ioli J. The cilia y epi helia and aqueous humo . In: Ha WM, Ed. Adle ’s Physiology o he eye. 9 h ed. S . Louis: Mosby-Yea book Inc
1992; pp. 118-47.
[167] Yamaguchi Y, Wa anabe T, Hi aka a A, Hida T. Localiza ion and on ogeny o aquapo in-1 and -4 exp ession in i is and cilia y epi helial cells
in a s. Cell Tissue Res 2006; 325(1): 101-9.
[h p://dx.doi.o g/10.1007/s00441-005-0122-z] [PMID: 16525835]
[168] Wis and PJ. Ca bonic anhyd ase in he an e io u ea o he abbi . Ac a Physiol Scand 1951; 24(2-3): 145-8.
[h p://dx.doi.o g/10.1111/j.1748-1716.1951. b00833.x] [PMID: 14894256]
[169] Tsukaguchi H, Tokui T, Mackenzie B, e al. A amily o mammalian Na+-dependen L-asco bic acid anspo e s. Na u e 1999; 399(6731):
70-5.
[h p://dx.doi.o g/10.1038/19986] [PMID: 10331392]
[170] Reddy VN. Dynamics o anspo sys ems in he eye. F iedenwald Lec u e. In es Oph halmol Vis Sci 1979; 18(10): 1000-18.
[PMID: 225285]
[171] Fi AD, Gonzalez G. Fluid mechanics o he human eye: aqueous humou low in he an e io chambe . Bull Ma h Biol 2006; 68(1): 53-71.
[h p://dx.doi.o g/10.1007/s11538-005-9015-2] [PMID: 16794921]
[172] Mu ay DL, Ba els SP. The ela ionship be ween aqueous humo low and an e io chambe p o ein concen a ion in abbi s. In es
Oph halmol Vis Sci 1993; 34(2): 370-6.
[PMID: 8440591]
[173] Lü jen-D ecoll E, Gabel BT, Tian B, Kau man PL. Ou low o aqueous humo . J Glaucoma 2001; 10(5)(Suppl. 1): S42-4.
[h p://dx.doi.o g/10.1097/00061198-200110001-00016] [PMID: 11890273]
[174] Tamm ER. The abecula meshwo k ou low pa hways: s uc u al and unc ional aspec s. Exp Eye Res 2009; 88(4): 648-55.
[h p://dx.doi.o g/10.1016/j.exe .2009.02.007] [PMID: 19239914]
[175] Tan JC, Pe e s DM, Kau man PL. Recen de elopmen s in unde s anding he pa hophysiology o ele a ed in aocula p essu e. Cu Opin
Oph halmol 2006; 17(2): 168-74.
[PMID: 16552252]
[176] B ubake RF. Measu emen o u eoscle al ou low in humans. J Glaucoma 2001; 10(5)(Suppl. 1): S45-8.
[h p://dx.doi.o g/10.1097/00061198-200110001-00017] [PMID: 11890274]
[177] Johnson M. ‘Wha con ols aqueous humou ou low esis ance?’. Exp Eye Res 2006; 82(4): 545-57.
[h p://dx.doi.o g/10.1016/j.exe .2005.10.011] [PMID: 16386733]
[178] Bill A. Some aspec s o aqueous humou d ainage. Eye (Lond) 1993; 7(P 1): 14-9.
[h p://dx.doi.o g/10.1038/eye.1993.4] [PMID: 8325404]
[179] Alm A, Nilsson SF. U eoscle al ou low--a e iew. Exp Eye Res 2009; 88(4): 760-8.
[h p://dx.doi.o g/10.1016/j.exe .2008.12.012] [PMID: 19150349]
[180] Fau sch MP, Johnson DH. Aqueous humo ou low: wha do we know? Whe e will i lead us? In es Oph halmol Vis Sci 2006; 47(10):
4181-7.
[h p://dx.doi.o g/10.1167/io s.06-0830] [PMID: 17003404]
[181] Nilsson SF. The u eoscle al ou low ou es. Eye (Lond) 1997; 11(P 2): 149-54.
[h p://dx.doi.o g/10.1038/eye.1997.43] [PMID: 9349404]
[182] Yücel YH, Johns on MG, Ly T, e al. Iden i ica ion o lympha ics in he cilia y body o he human eye: a no el “u eolympha ic” ou low
pa hway. Exp Eye Res 2009; 89(5): 810-9.
[h p://dx.doi.o g/10.1016/j.exe .2009.08.010] [PMID: 19729007]
[183] Wein eb RN. U eoscle al ou low: he o he ou low pa hway. J Glaucoma 2000; 9(5): 343-5.
[h p://dx.doi.o g/10.1097/00061198-200010000-00001] [PMID: 11039734]
[184] Zhang K, Zhang L, Wein eb RN. Oph halmic d ug disco e y: no el a ge s and mechanisms o e inal diseases and glaucoma. Na Re D ug
Disco 2012; 11(7): 541-59.
[h p://dx.doi.o g/10.1038/n d3745] [PMID: 22699774]
RAS in he Eye The Open Oph halmology Jou nal, 2017, Volume 11 139
[185] Meh a A, Iye L, Pa ma S, Shah G, Goyal R. Oculohypo ensi e e ec o pe indop il in acu e and ch onic models o glaucoma in abbi s. Can
J Physiol Pha macol 2010; 88(5): 595-600.
[h p://dx.doi.o g/10.1139/Y10-026] [PMID: 20555429]
[186] Inoue T, Yokoyoma T, Koike H. The e ec o angio ensin II on u eoscle al ou low in abbi s. Cu Eye Res 2001; 23(2): 139-43.
[h p://dx.doi.o g/10.1076/cey .23.2.139.5470] [PMID: 11840353]
[187] Shen F, Zhang L, Liu T. [E ec s o angio ensin II on he 3H-TdR inco po a ion and syn hesis o collagen in cul u ed bo ine abecula
meshwo k cells]. Yan Ke Xue Bao 2001; 17(4): 209-12.
[PMID: 12567506]
[188] Rei same HA, Kiel JW. Rela ionship be ween cilia y blood low and aqueous p oduc ion in abbi s. In es Oph halmol Vis Sci 2003; 44(9):
3967-71.
[h p://dx.doi.o g/10.1167/io s.03-0088] [PMID: 12939316]
[189] Lo i VJ, Pawlowski N. P os aglandins media e he ocula hypo ensi e ac ion o he angio ensin con e ing enzyme inhibi o MK-422
(enalap ila ) in A ican g een monkeys. J Ocul Pha macol 1990; 6(1): 1-7.
[h p://dx.doi.o g/10.1089/jop.1990.6.1] [PMID: 2163428]
[190] Nilsson SF, Samuelsson M, Bill A, S je nschan z J. Inc eased u eoscle al ou low as a possible mechanism o ocula hypo ension caused by
p os aglandin F2 alpha-1-isop opyles e in he cynomolgus monkey. Exp Eye Res 1989; 48(5): 707-16.
[h p://dx.doi.o g/10.1016/0014-4835(89)90011-0] [PMID: 2737263]
[191] Wein eb RN, To is CB, Gabel BT, Lindsey JD, Kau man PL. E ec s o p os aglandins on he aqueous humo ou low pa hways. Su
Oph halmol 2002; 47(Suppl. 1): S53-64.
[h p://dx.doi.o g/10.1016/S0039-6257(02)00306-5] [PMID: 12204701]
[192] Momose N, Fukuo K, Mo imo o S, Ogiha a T. Cap op il inhibi s endo helin-1 sec e ion om endo helial cells h ough b adykinin.
Hype ension 1993; 21(6 P 2): 921-4.
[h p://dx.doi.o g/10.1161/01.HYP.21.6.921] [PMID: 8389325]
[193] Hae lige IO, Flamme J, Lüsche TF. Ni ic oxide and endo helin-1 a e impo an egula o s o human oph halmic a e y. In es Oph halmol
Vis Sci 1992; 33(7): 2340-3.
[PMID: 1607246]
[194] Yao K, Tschudi M, Flamme J, Lüsche TF. Endo helium-dependen egula ion o ascula one o he po cine oph halmic a e y. In es
Oph halmol Vis Sci 1991; 32(6): 1791-8.
[PMID: 2032802]
[195] Quigley HA, Pi ha IF, Welsbie DS, e al. Losa an ea men p o ec s e inal ganglion cells and al e s scle al emodeling in expe imen al
glaucoma. PLoS One 2015; 10(10): e0141137.
[h p://dx.doi.o g/10.1371/jou nal.pone.0141137] [PMID: 26505191]
[196] Yang H, Hi ooka K, Fukuda K, Shi aga F. Neu op o ec i e e ec s o angio ensin II ype 1 ecep o blocke in a a model o ch onic
glaucoma. In es Oph halmol Vis Sci 2009; 50(12): 5800-4.
[h p://dx.doi.o g/10.1167/io s.09-3678] [PMID: 19608537]
[197] Sha i NA. No el po en ial ea men modali ies o ocula hype ension: ocus on angio ensin and b adykinin sys em axes. J Ocul Pha macol
The 2015; 31(3): 131-45.
[h p://dx.doi.o g/10.1089/jop.2014.0114] [PMID: 25599263]
[198] Fou eaux G, Noguei a BS, Cou inho DC, Raizada MK, Noguei a JC, Fe ei a AJ. Ac i a ion o endogenous angio ensin con e ing enzyme 2
p e en s ea ly inju ies induced by hype glycemia in a e ina. B az J Med Biol Res 2015; 48(12): 1109-14.
[h p://dx.doi.o g/10.1590/1414-431X20154583] [PMID: 26421871]
[199] Solinski HJ, Gude mann T, B ei A. Pha macology and signaling o MAS- ela ed G p o ein-coupled ecep o s. Pha macol Re 2014; 66(3):
570-97.
[h p://dx.doi.o g/10.1124/p .113.008425] [PMID: 24867890]
[200] Luh ala S, Vaajanen A, Oksala O, Valjakka J, Vapaa alo H. Ac i i ies o angio ensin-con e ing enzymes ACE1 and ACE2 and inhibi ion by
bioac i e pep ides in po cine ocula issues. J Ocul Pha macol The 2009; 25(1): 23-8.
[h p://dx.doi.o g/10.1089/jop.2008.0081] [PMID: 19232015]
[201] San os RA, Simoes e Sil a AC, Ma ic C, e al. Angio ensin-(1-7) is an endogenous ligand o he G p o ein-coupled ecep o Mas. P oc Na l
Acad Sci USA 2003; 100(14): 8258-63.
[h p://dx.doi.o g/10.1073/pnas.1432869100] [PMID: 12829792]
[202] Mac i FJ. The ac ion o angio ensin on in aocula p essu e. A ch Oph halmol 1965; 73: 528-39.
[h p://dx.doi.o g/10.1001/a choph .1965.00970030530016] [PMID: 14270142]
[203] Capponi AM, Lew PD, Jo no L, Vallo on MB. Co ela ion be ween cy osolic ee Ca2+ and aldos e one p oduc ion in bo ine ad enal
glome ulosa cells. E idence o a di e ence in he mode o ac ion o angio ensin II and po assium. J Biol Chem 1984; 259(14): 8863-9.
[PMID: 6746627]
[204] Langman MJ, Lancashi e RJ, Cheng KK, S ewa PM. Sys emic hype ension and glaucoma: mechanisms in common and co-occu ence. B J
Oph halmol 2005; 89(8): 960-3.
140 The Open Oph halmology Jou nal, 2017, Volume 11 Holappa e al.
[h p://dx.doi.o g/10.1136/bjo.2004.053397] [PMID: 16024843]
[205] G unwald JE, Ri a CE, S one RA, Kea es EU, Pe ig BL. Re inal au o egula ion in open-angle glaucoma. Oph halmology 1984; 91(12):
1690-4.
[h p://dx.doi.o g/10.1016/S0161-6420(84)34091-X] [PMID: 6521997]
[206] Pil z-seymou JR, G unwald JE, Ha ip asad SM, Dupon J. Op ic ne e blood low is diminished in eyes o p ima y open-angle glaucoma
suspec s. Am J Oph halmol 2001; 132(1): 63-9.
[h p://dx.doi.o g/10.1016/S0002-9394(01)00871-6] [PMID: 11438055]
[207] Hay eh SS, Zimme man MB, Podhajsky P, Alwa d WL. Noc u nal a e ial hypo ension and i s ole in op ic ne e head and ocula ischemic
diso de s. Am J Oph halmol 1994; 117(5): 603-24.
[h p://dx.doi.o g/10.1016/S0002-9394(14)70067-4] [PMID: 8172267]
[208] Ma in Ga cia PJ, Ma in-Cas año ME. Angio ensin II- ela ed hype ension and eye diseases. Wo ld J Ca diol 2014; 6(9): 968-84.
[h p://dx.doi.o g/10.4330/wjc. 6.i9.968] [PMID: 25276298]
[209] F ank RN. Diabe ic e inopa hy. N Engl J Med 2004; 350(1): 48-58.
[h p://dx.doi.o g/10.1056/NEJM a021678] [PMID: 14702427]
[210] Ha indhana udhi T, Maue M, Klein R, Zinman B, Sinaiko A, Ca amo i ML. Bene i s o Renin-Angio ensin blockade on e inopa hy in ype
1 diabe es a y wi h glycemic con ol. Diabe es Ca e 2011; 34(8): 1838-42.
[h p://dx.doi.o g/10.2337/dc11-0476] [PMID: 21715517]
[211] Bolinge MT, An one i DA. Mo ing pas an i-VEGF: no el he apies o ea ing diabe ic e inopa hy. In J Mol Sci 2016; 17(9): E1498.
[h p://dx.doi.o g/10.3390/ijms17091498] [PMID: 27618014]
[212] Ta JM, Kaul K, Chop a M, Kohne EM, Chibbe R. Pa hophysiology o diabe ic e inopa hy 2013.
[h p://dx.doi.o g/10.1155/2013/343560]
[213] Sjølie AK, Dodson P, Hobbs FR. Does enin-angio ensin sys em blockade ha e a ole in p e en ing diabe ic e inopa hy? A clinical e iew.
In J Clin P ac 2011; 65(2): 148-53.
[h p://dx.doi.o g/10.1111/j.1742-1241.2010.02552.x] [PMID: 21235695]
[214] Wilkinson CP, Fe is FL III, Klein RE, e al. P oposed in e na ional clinical diabe ic e inopa hy and diabe ic macula edema disease se e i y
scales. Oph halmology 2003; 110(9): 1677-82.
[h p://dx.doi.o g/10.1016/S0161-6420(03)00475-5] [PMID: 13129861]
[215] I ano a T, Jalil A, An oniou Y, Bishop PN, Vallejo-Ga cia JL, Pa on N. Vi ec omy o p ima y symp oma ic i eous opaci ies: an
e idence-based e iew. Eye (Lond) 2016; 30(5): 645-55.
[h p://dx.doi.o g/10.1038/eye.2016.30] [PMID: 26939559]
[216] Cle mon A, Bu sell SE, Feene EP. Role o he angio ensin II ype 1 ecep o in he pa hogenesis o diabe ic e inopa hy: e ec s o blood
p essu e con ol and beyond. J Hype ens Suppl 2006; 24(1): S73-80.
[h p://dx.doi.o g/10.1097/01.hjh.0000220410.69116. 8] [PMID: 16601577]
[217] Maue M, Zinman B, Ga dine R, e al. Renal and e inal e ec s o enalap il and losa an in ype 1 diabe es. N Engl J Med 2009; 361(1):
40-51.
[h p://dx.doi.o g/10.1056/NEJMoa0808400] [PMID: 19571282]
[218] Wilkinson-Be ka JL, Tan G, Jawo ski K, Ninko ic S. Valsa an bu no a enolol imp o es ascula pa hology in diabe ic Ren-2 a e ina. Am
J Hype ens 2007; 20(4): 423-30.
[h p://dx.doi.o g/10.1016/j.amjhype .2006.09.018] [PMID: 17386351]
[219] Funa su H, Yamashi a H, Nakanishi Y, Ho i S. Angio ensin II and ascula endo helial g ow h ac o in he i eous luid o pa ien s wi h
p oli e a i e diabe ic e inopa hy. B J Oph halmol 2002; 86(3): 311-5.
[h p://dx.doi.o g/10.1136/bjo.86.3.311] [PMID: 11864890]
[220] Funa su H, Yamashi a H, Ikeda T, Nakanishi Y, Ki ano S, Ho i S. Angio ensin II and ascula endo helial g ow h ac o in he i eous luid
o pa ien s wi h diabe ic macula edema and o he e inal diso de s. Am J Oph halmol 2002; 133(4): 537-43.
[h p://dx.doi.o g/10.1016/S0002-9394(02)01323-5] [PMID: 11931788]
[221] Schi man R, Fishe L, Nussbaum J, Edwa ds P, Scicli G. P o enin and enin le els in he i eous o human eyes wi h and wi hou
p oli e a i e diabe ic e inopa hy. In es Oph halmol Vis Sci 1992; 33: 1362.
[222] Nagisa Y, Shin ani A, Nakagawa S. The angio ensin II ecep o an agonis candesa an cilexe il (TCV-116) amelio a es e inal diso de s in
a s. Diabe ologia 2001; 44(7): 883-8.
[h p://dx.doi.o g/10.1007/s001250100556] [PMID: 11508274]
[223] O ani A, Takagi H, Suzuma K, Honda Y. Angio ensin II po en ia es ascula endo helial g ow h ac o -induced angiogenic ac i i y in e inal
mic ocapilla y endo helial cells. Ci c Res 1998; 82(5): 619-28.
[h p://dx.doi.o g/10.1161/01.RES.82.5.619] [PMID: 9529167]
[224] Fe nandez LA, Twickle J, Mead A. Neo ascula iza ion p oduced by angio ensin II. J Lab Clin Med 1985; 105(2): 141-5.
[PMID: 2579174]
[225] Aiello LP, Bu sell SE, Cle mon A, e al. Vascula endo helial g ow h ac o -induced e inal pe meabili y is media ed by p o ein kinase C in
i o and supp essed by an o ally e ec i e be a-iso o m-selec i e inhibi o . Diabe es 1997; 46(9): 1473-80.
RAS in he Eye The Open Oph halmology Jou nal, 2017, Volume 11 141
[h p://dx.doi.o g/10.2337/diab.46.9.1473] [PMID: 9287049]
[226] Haque R, Hu EH, Fa ell AN, Iu one PM, Howell JC. Mic oRNA-152 ep esses VEGF and TGFβ1 exp essions h ough pos - ansc ip ional
inhibi ion o (P o) enin ecep o in human e inal endo helial cells. Mol Vis 2015; 21: 224-35.
[PMID: 25802486]
[227] Kanda A, Ishida S. The i eous enin–angio ensin sys em is media ed by soluble (p o) enin ecep o in diabe ic e inopa hy: A new
implica ion o he ecep o -associa ed p o enin sys em. Taiwan J Oph halmol 2013; 3: 51-3.
[h p://dx.doi.o g/10.1016/j. jo.2013.04.004]
[228] Kanda A, Noda K, Sai o W, Ishida S. (P o) enin ecep o is associa ed wi h angiogenic ac i i y in p oli e a i e diabe ic e inopa hy.
Diabe ologia 2012; 55(11): 3104-13.
[h p://dx.doi.o g/10.1007/s00125-012-2702-2] [PMID: 22930161]
[229] Sa o uka S, Ichiha a A, Nagai N, e al. (P o) enin ecep o -media ed signal ansduc ion and issue enin-angio ensin sys em con ibu e o
diabe es-induced e inal in lamma ion. Diabe es 2009; 58(7): 1625-33.
[h p://dx.doi.o g/10.2337/db08-0254] [PMID: 19389828]
[230] Vincen F, Bonnin P, Clemessy M, e al. Angio ensinogen delays angiogenesis and umo g ow h o hepa oca cinoma in ansgenic mice.
Cance Res 2009; 69(7): 2853-60.
[h p://dx.doi.o g/10.1158/0008-5472.CAN-08-2484] [PMID: 19318581]
[231] Es acio RO, Je e s BW, Hia WR, Bigge s a SL, Gi o d N, Sch ie RW. The e ec o nisoldipine as compa ed wi h enalap il on
ca dio ascula ou comes in pa ien s wi h non-insulin-dependen diabe es and hype ension. N Engl J Med 1998; 338(10): 645-52.
[h p://dx.doi.o g/10.1056/NEJM199803053381003] [PMID: 9486993]
[232] Lewis EJ, Hunsicke LG, Bain RP, Rohde RD. The e ec o angio ensin-con e ing-enzyme inhibi ion on diabe ic neph opa hy. N Engl J
Med 1993; 329(20): 1456-62.
[h p://dx.doi.o g/10.1056/NEJM199311113292004] [PMID: 8413456]
[233] Jonas JB, Hay eh SS, Ma us P. In luence o a e ial hype ension and die -induced a he oscle osis on macula d usen. G ae es A ch Clin Exp
Oph halmol 2003; 241(2): 125-34.
[h p://dx.doi.o g/10.1007/s00417-002-0615-3] [PMID: 12605267]
[234] Wang B, Wang F, Zhang Y, e al. E ec s o RAS inhibi o s on diabe ic e inopa hy: a sys ema ic e iew and me a-analysis. Lance Diabe es
Endoc inol 2015; 3(4): 263-74.
[h p://dx.doi.o g/10.1016/S2213-8587(14)70256-6] [PMID: 25660574]
[235] Tigh blood p essu e con ol and isk o mac o ascula and mic o ascula complica ions in ype 2 diabe es: UKPDS 38. BMJ 1998;
317(7160): 703-13.
[h p://dx.doi.o g/10.1136/bmj.317.7160.703] [PMID: 9732337]
[236] Cha u edi N, Sjolie AK, S ephenson JM, e al. E ec o lisinop il on p og ession o e inopa hy in no mo ensi e people wi h ype 1 diabe es.
The EUCLID S udy G oup. EURODIAB Con olled T ial o Lisinop il in Insulin-Dependen Diabe es Melli us. Lance 1998; 351(9095):
28-31.
[h p://dx.doi.o g/10.1016/S0140-6736(97)06209-0] [PMID: 9433426]
[237] Sa o uka S, Ichiha a A, Nagai N, e al. Role o nonp o eoly ically ac i a ed p o enin in pa hologic, bu no physiologic, e inal
neo ascula iza ion. In es Oph halmol Vis Sci 2007; 48(1): 422-9.
[h p://dx.doi.o g/10.1167/io s.06-0534] [PMID: 17197563]
[238] Fle che EL, Phipps JA, Wa d MM, Vessey KA, Wilkinson-Be ka JL. The enin-angio ensin sys em in e inal heal h and disease: I s in luence
on neu ons, glia and he ascula u e. P og Re in Eye Res 2010; 29(4): 284-311.
[h p://dx.doi.o g/10.1016/j.p e eye es.2010.03.003] [PMID: 20380890]
[239] Nagai N, Oike Y, Izumi-Nagai K, e al. Supp ession o cho oidal neo ascula iza ion by inhibi ing angio ensin-con e ing enzyme: minimal
ole o b adykinin. In es Oph halmol Vis Sci 2007; 48(5): 2321-6.
[h p://dx.doi.o g/10.1167/io s.06-1296] [PMID: 17460297]
[240] P addaude F, Cousins SW, Pêche C, Ma in-Cas año ME. Angio ensin II-induced hype ension egula es AT1 ecep o sub ypes and
ex acellula ma ix u no e in mouse e inal pigmen epi helium. Exp Eye Res 2009; 89(1): 109-18.
[h p://dx.doi.o g/10.1016/j.exe .2009.02.020] [PMID: 19281810]
[241] S ike GE, P addaude F, Alcaza O, Cousins SW, Ma in-Cas año ME. Regula ion o angio ensin II ecep o s and ex acellula ma ix
u no e in human e inal pigmen epi helium: ole o angio ensin II. Am J Physiol Cell Physiol 2008; 295(6): C1633-46.
[h p://dx.doi.o g/10.1152/ajpcell.00092.2008] [PMID: 18923060]
[242] Ishida S. [Li es yle- ela ed diseases and an i-aging oph halmology: supp ession o e inal and cho oidal pa hologies by inhibi ing enin-
angio ensin sys em and in lamma ion]. Nippon Ganka Gakkai Zasshi 2009; 113(3): 403-22.
[PMID: 19348185]
[243] Sa o uka S, Ichiha a A, Nagai N, e al. (P o) enin ecep o p omo es cho oidal neo ascula iza ion by ac i a ing i s signal ansduc ion and
issue enin-angio ensin sys em. Am J Pa hol 2008; 173(6): 1911-8.
[h p://dx.doi.o g/10.2353/ajpa h.2008.080457] [PMID: 18974301]
[244] Hikichi T, Mo i F, Takamiya A, e al. Inhibi o y e ec o losa an on lase -induced cho oidal neo ascula iza ion in a s. Am J Oph halmol
2001; 132(4): 587-9.
142 The Open Oph halmology Jou nal, 2017, Volume 11 Holappa e al.
[h p://dx.doi.o g/10.1016/S0002-9394(01)01139-4] [PMID: 11589891]
[245] Nagai N, Oike Y, Izumi-Nagai K, e al. Angio ensin II ype 1 ecep o -media ed in lamma ion is equi ed o cho oidal neo ascula iza ion.
A e ioscle Th omb Vasc Biol 2006; 26(10): 2252-9.
[h p://dx.doi.o g/10.1161/01.ATV.0000240050.15321. e] [PMID: 16888236]
[246] Nabah YN, Ma eo T, Es ellés R, e al. Angio ensin II induces neu ophil accumula ion in i o h ough gene a ion and elease o CXC
chemokines. Ci cula ion 2004; 110(23): 3581-6.
[h p://dx.doi.o g/10.1161/01.CIR.0000148824.93600.F3] [PMID: 15569833]
[247] Buschini E, Fea AM, La ia CA, e al. Recen de elopmen s in he managemen o d y age- ela ed macula degene a ion. Clin Oph halmol
2015; 9: 563-74.
[h p://dx.doi.o g/10.2147/OPTH.S59724] [PMID: 25878491]
[248] Mul icen e T ial o C yo he apy o Re inopa hy o P ema u i y: oph halmological ou comes a 10 yea s. A ch Oph halmol 2001; 119(8):
1110-8.
[h p://dx.doi.o g/10.1001/a choph .119.8.1110] [PMID: 11483076]
[249] Lu y GA, Chan-Ling T, Phelps DL, e al. P oceedings o he Thi d In e na ional Symposium on Re inopa hy o P ema u i y: an upda e on
ROP om he lab o he nu se y (No embe 2003, Anaheim, Cali o nia). Mol Vis 2006; 12: 532-80.
[PMID: 16735995]
[250] Au a a R, Senko á K, Holouso á M, K ejcí o á I, Dolezel Z, Bo ek I. [E ec s o in a i eal pegap anib o be acizumab and lase in
ea men o h eshold e inopa hy o p ema u i y in zone I and pos e io zone II-- ou yea s esul s]. Cesk Slo O almol 2012; 68(1): 29-36.
[PMID: 22679695]
[251] Beha y KD, Valencia GB, Lazza o DR, A anda JV. Pha macologic in e en ions o he p e en ion and ea men o e inopa hy o
p ema u i y. Semin Pe ina ol 2016; 40(3): 189-202.
[h p://dx.doi.o g/10.1053/j.sempe i.2015.12.006] [PMID: 26831641]
[252] Yoko a H, Nagaoka T, Mo i F, e al. P o enin le els in e inopa hy o p ema u i y. Am J Oph halmol 2007; 143(3): 531-3.
[h p://dx.doi.o g/10.1016/j.ajo.2006.10.046] [PMID: 17317409]
[253] Mo a ski CJ, Kelly DJ, Coope ME, e al. Re inal neo ascula iza ion is p e en ed by blockade o he enin-angio ensin sys em. Hype ension
2000; 36(6): 1099-104.
[h p://dx.doi.o g/10.1161/01.HYP.36.6.1099] [PMID: 11116132]
[254] Sa los S, Rizkalla B, Mo a ski CJ, Cao Z, Coope ME, Wilkinson-Be ka JL. Re inal angiogenesis is media ed by an in e ac ion be ween he
angio ensin ype 2 ecep o , VEGF, and angiopoie in. Am J Pa hol 2003; 163(3): 879-87.
[h p://dx.doi.o g/10.1016/S0002-9440(10)63448-7] [PMID: 12937129]
[255] Downie LE, Pian a MJ, Ving ys AJ, Wilkinson-Be ka JL, Fle che EL. AT1 ecep o inhibi ion p e en s as ocy e degene a ion and es o es
ascula g ow h in oxygen-induced e inopa hy. Glia 2008; 56(10): 1076-90.
[h p://dx.doi.o g/10.1002/glia.20680] [PMID: 18442090]
[256] Lonchamp M, Pennel L, Duhaul J. Hype oxia/no moxia-d i en e inal angiogenesis in mice: a ole o angio ensin II. In es Oph halmol Vis
Sci 2001; 42(2): 429-32.
[PMID: 11157878]
[257] Tadesse M, Yan Y, Yossuck P, Higgins RD. Cap op il imp o es e inal neo ascula iza ion ia endo helin-1. In es Oph halmol Vis Sci 2001;
42(8): 1867-72.
[PMID: 11431455]
[258] O ani A, Takagi H, Oh H, e al. Angio ensin II-s imula ed ascula endo helial g ow h ac o exp ession in bo ine e inal pe icy es. In es
Oph halmol Vis Sci 2000; 41(5): 1192-9.
[PMID: 10752960]
© 2017 Holappa e al.
This is an open access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional Public License (CC-BY 4.0), a
copy o which is a ailable a : h ps://c ea i ecommons.o g/licenses/by/4.0/legalcode. This license pe mi s un es ic ed use, dis ibu ion, and
ep oduc ion in any medium, p o ided he o iginal au ho and sou ce a e c edi ed.