Regulation of Male Fertility by the Renin-Angiotensin System

In e na ional Jou nal o
Molecula Sciences
Re iew
Regula ion o Male Fe ili y by he Renin-
Angio ensin Sys em
Ma a Gianzo 1and Ne ea Subi án1,2,3,*
1
Depa men o Physiology, Facul y o Medicine and Nu se y, Uni e si y o he Basque Coun y (UPV/EHU),
48940 Leioa, Spain; [email p o ec ed]
2Inno a ion in Assis ed Rep oduc ion G oup, Bioc uces-Bizkaia Heal h Resea ch Ins i u e,
48903 Ba akaldo, Spain
3Resea ch and De elopmen Depa men , MEPRO Medical Rep oduc i e Solu ions,
20009 San Sebas ian, Spain
*Co espondence: ne [email p o ec ed]
Recei ed: 30 Sep embe 2020; Accep ed: 19 Oc obe 2020; Published: 26 Oc obe 2020


Abs ac :
The enin-angio ensin sys em (RAS) is a pep idic sys em known mainly o i s oles in he
main enance o blood p essu e and elec oly e and luid homeos asis. Howe e , se e al issues and
cells ha e been desc ibed o possess an in insic RAS ha ac s locally h ough di e en pa ac ine
and au oc ine mechanisms. In he male ep oduc i e sys em, se e al componen s o his sys em
ha e been obse ed in a ious o gans and issues, such as he es es, spe ma ozoa and seminal luid.
Some unc ions a ibu ed o his local RAS a e main enance o seminal plasma elec oly es, egula ion
o s e oidogenesis and spe ma ogenesis, and spe m unc ions. Howe e , hei speci ic ac ions in
hese loca ions a e no ully unde s ood. The e o e, a deep knowledge o he unc ions o he RAS a
bo h he es icula and seminal le els could cla i y i s oles in male in e ili y and spe m physiology,
and he di e en RAS elemen s could be used o design ools enabling he diagnosis and/o ea men
o male in e ili y.
Keywo ds: Renin-angio ensin sys em; male in e ili y; angio ensin; enin; es is; spe ma ozoa
1. In oduc ion
Acco ding o he Wo ld Heal h O ganiza ion (WHO), in e ili y is de ined as he inabili y o
achie e p egnancy a e a yea o no mal sexual ela ionships wi hou he use o any con acep i e
me hod. In e ili y is one o he mos p e alen ch onic heal h diso de s in ol ing young adul s,
caused by ad anced pa en al age and ou li es yle among o he ac o s [
1
]. Su e ing one in six couples
o ep oduc i e age, his disease has a cu en es ima ed p e alence o 14% wo ldwide and i a ec s
bo h men and women; in ac , 50% o cases a e due o he emale pa ne , and he o he 50% a e due o
he male pa ne [1,2].
Male in e ili y is mainly caused by ana omical de ec s, gene ic diseases and inju ies, as well as
es icula spe m and ho monal dys unc ion [
3
–
5
]. The p oduc ion o ully unc ional spe ma ozoa
capable o mo emen and e iliza ion is unde s ic endoc ine, pa ac ine and au oc ine egula ion.
De egula ion o his ho monal con ol o al e a ions in he di e en key cellula communica ion
sys ems can cause male in e ili y [
4
,
5
]. Howe e , he p ecise causes o male in e ili y emain
unexplained in app oxima ely 30% o cases, as many ep oduc i e de ec s canno be de ec ed wi h
cu en diagnos ic me hods [2].
In . J. Mol. Sci. 2020,21, 7943; doi:10.3390/ijms21217943 www.mdpi.com/jou nal/ijms
In . J. Mol. Sci. 2020,21, 7943 2 o 18
RAS is a communica ion sys em ha is epo ed o play a key ole in he egula ion o ep oduc i e
unc ion in bo h males and emales [
6
,
7
]. In he emale ep oduc i e sys em, he RAS is in ol ed
in many physiological and physiopa hological p ocesses, such as oocy e ma u a ion and quali y
con ol, endome ial lining p oduc ion and/o ho mone p oduc ion, polycys ic o a y synd ome,
o a ian hype s imula ion synd ome and o a ian o endome ial cance [
7
]. In his e iew, we ocus on
p o iding an upda e o ecen impo an indings o he ole o RAS in male ep oduc i e unc ion,
which is capable o he egula ion o male e ili y a mul iple le els [
6
,
8
,
9
]. In ac , mul iple RAS amily
membe s a e exp essed on di e en male ep oduc i e issues, such as he es es and semen, whe e hey
egula e male e ili y, ac ing syne gis ically wi h and/o independen ly o sys emic RAS [6].
2. The Renin-Angio ensin Sys em (RAS)
The RAS is a pep idic sys em wi h endoc ine cha ac e is ics known mainly o i s impo ance
in he main enance o blood p essu e (BP) and elec oly e and luid homeos asis [
6
]. This sys em is
canonically conside ed o be a ci cula ing ho monal sys em ha exe s i s unc ions h ough angio ensin
II (Ang II) and aldos e one. This pa hway is ac i a ed when enin is eleased by he kidneys in o
he bloods eam in esponse o dec eased BP, sympa he ic ne ous sys em ac i a ion and/o sodium
deple ion [
6
]. This enin ac s on angio ensinogen (AGT) o hepa ic o igin, o ming angio ensin I (Ang I).
The inac i e Ang I pep ide is hyd olysed by he angio ensin-con e ing enzyme (ACE), gi ing ise
o he pep ide wi h he highes ac i i y in his sys em, Ang II, which ul ima ely exe s i s ac ion by
in e ac ing wi h Ang II ype 1 and 2 ecep o s (AT1R and AT2R) [
6
,
10
]. Ang II signalling p oduces
se e al esponses, such as asocons ic ion o he pe iphe al ci cula ion, inc eased sympa he ic sys em
ac i i y, elease o asop essin, inc eased ca diac ch ono opism, and elease o aldos e one om
he ad enal co ex, which can es o e blood olume and p essu e. In u n, Ang II i sel inhibi s he
syn hesis and elease o enin, egula ing he ac i a ion o he RAS [6].
This adi ional concep o he RAS has been e ised due o he disco e y o new RAS amily
membe s, which has p o ided e idence o he exis ence o new non-canonical pa hways o his sys em
(Figu e 1). P incipally, he ield was ede ined by he disco e y o ACE2, an ACE homologue ha
clea es Ang II o gene a e angio ensin 1–7 (Ang 1–7), which ac i a es he Mas ecep o (MasR). La e ,
he lis o pa hway membe s was ex ended when ano he agmen o Ang II, Ang 3–8 (also called
Ang IV), was obse ed; Ang 3–8 ac s on i s own ecep o , insulin- egula ed aminopep idase (IRAP,
also called AT4R) [
11
]. Finally, he (p o) enin ecep o (PRR), on which p o enin and enin ac di ec ly,
was desc ibed [
12
]. The appea ance o all hese new RAS componen s has implied ha his esponse
sys em in ol es complex in e play among a ious angio ensin ecep o s and hei signalling pa hways,
as well as ecep o -like ac i i y o RAS enzymes ha can p omo e Ang II-independen in acellula
enzyma ic pa hways [11].
In ecen yea s, a en ion has also been paid o e idence o a widesp ead local issue RAS. This new
concep eme ged a e disco e y o he exis ence o di e en RAS amily membe s in se e al issues
ha a e able o egula e se e al speci ic unc ions, wo king syne gis ically wi h o independen ly o he
sys emic RAS [
6
,
11
]. These local RASs a e mainly cha ac e ized by (1) he p esence o di e en RAS
componen s, such as AGT and con e ing enzymes; (2) local syn hesis o Ang II and o he angio ensins;
and (3) he p esence o he speci ic ecep o s. Howe e , he local p oduc ion o bioac i e pep ides is no
necessa ily dependen on local exp ession o all componen s o he local issue RAS, since componen s
om he ci cula ion, such as enin, can also be aken up [
7
]. In ac , i has been obse ed ha local RASs
a e p esen in a wide ange o sys ems, o gans, and issues, such as he kidneys, b ain, ca dio ascula
sys em, pi ui a y gland, adipose issue, skin, ad enal gland, and emale and male ep oduc i e sys ems;
hese RASs play impo an oles in many physiological p ocesses, such as, cell g ow h, ex acellula
ma ix o ma ion, ascula p oli e a ion, endo helial unc ion and apop osis [
11
,
13
]. Fu he mo e,
local RASs can also in e ac wi h o he signalling pa hways, including hose in ol ing achykinins,
enkephalins, ni ic oxide (NO), p os aglandins o cellula phospha ases [6,13].
In . J. Mol. Sci. 2020,21, 7943 3 o 18
In .J.Mol.Sci.2020,21,xFORPEERREVIEW3o 18

Figu e1.Cu en  iewo  heRAS.Canonicalo sys emicpa hwayisshowninblue,while heno‐
canonicalaxesa eshownin ed.Pep ideabb e ia ions:AGT,angio ensinogen;AngI,angio ensinI;
AngII,angio ensinII;AngIII,angio ensinIII;AngIV,angio ensin(3–8)o IV;Ang(1–9),angio ensin
(1–9);Ang(1–7),angio ensin(1–7).Recep o abb e ia ions:AT1R,AngII ecep o  ype1;AT2R,Ang
II ype2 ecep o ;AT4R/IRAP,AngIV ecep o ;MasR,Ang ecep o (1–7)o Mas ecep o ;PRR,
(p o) enin ecep o .Enzymeabb e ia ions:ACE,angio ensin‐con e ingenzyme;ACE2,angio ensin‐
con e ingenzyme2;NEP,neu alendopep idase;APA,aminopep idaseA;APN,aminopep idase
N;APB,aminopep idaseB.
Alongwi h helocalsyn hesisandup akeo RASelemen sby issues, he eisinc easing
e idence ha bo hsyn hesisandup akealsooccu a  hecellula le el,whichsugges sanew
mechanismo ac ion o aphysiologicalsys emcalled hein acellula RAS[14].Thisnew
in acellula sys emischa ac e izedby hep esenceo di e en RAScomponen sinside hecelland
by hesyn hesiso AngIIa anin acellula si e.Theconcep o  hissys emisbasedon1)obse a ion
o  heexis enceo di e seiso o mso AGTand enin(asa esul o glycosyla ionandal e na i e
splicing, espec i ely)anddi e en  o mso ACE(in acellula andsec e ed),2) heexis enceo 
al e na i eenzymes o  hesyn hesiso AngII(suchasca hepsinandchymase),and3)in acellula 
de ec iono  hesecomponen sunde pa icula cellula condi ions.Inaddi ion, hesecomponen s
mus beable omedia ebiologicale ec s omanin acellula loca ion obe unc ionally ele an 
[15].In ac ,changesincells uc u eandgene ansc ip ionha ebeen epo ed oinduce he
mobiliza iono in acellula calciumdeposi sands imula e heg ow ho di e en cell ypesha e
been epo ed[13,15].Inspi eo  ha , he unc ional oleso  hein acellula RASinphysiologyand
pa hophysiologyha eno ye been ullyelucida ed.
2.1.Axes ha Compose heRAS
Nowadays,RAShasbeendesc ibedasacomplexsys emcomposedby hecanonicalaxisaswell
as henon‐canonicalaxes(Figu e1),whosecomponen sa ewidelyexp essedinallcell ypesand
o gansinhumans.The e o e,RASplaysimpo an  olesinnume ousphysiologicale en s,suchas
enal,neu onal,ca diac,panc ea ic, ascula ,ad enal,pi ui a y,cogni i e,ageing‐ ela ed,
in lamma o yand ep oduc i ep ocesses[16].No ably,oneo  hemos  ele an  unc ionso  he
RASisi spa icipa ionin a iousp ocesses ela ed omale e ili y[7,8,17,18].
Figu e 1.
Cu en iew o he RAS. Canonical o sys emic pa hway is shown in blue, while he
no-canonical axes a e shown in ed. Pep ide abb e ia ions: AGT, angio ensinogen; Ang I, angio ensin I;
Ang II, angio ensin II; Ang III, angio ensin III; Ang IV, angio ensin (3–8) o IV; Ang (1–9), angio ensin
(1–9); Ang (1–7), angio ensin (1–7). Recep o abb e ia ions: AT1R, Ang II ecep o ype 1; AT2R, Ang II
ype 2 ecep o ; AT4R/IRAP, Ang IV ecep o ; MasR, Ang ecep o (1–7) o Mas ecep o ; PRR, (p o) enin
ecep o . Enzyme abb e ia ions: ACE, angio ensin-con e ing enzyme; ACE2, angio ensin-con e ing
enzyme 2; NEP, neu al endopep idase; APA, aminopep idase A; APN, aminopep idase N; APB,
aminopep idase B.
Along wi h he local syn hesis and up ake o RAS elemen s by issues, he e is inc easing e idence
ha bo h syn hesis and up ake also occu a he cellula le el, which sugges s a new mechanism o
ac ion o a physiological sys em called he in acellula RAS [
14
]. This new in acellula sys em is
cha ac e ized by he p esence o di e en RAS componen s inside he cell and by he syn hesis o Ang
II a an in acellula si e. The concep o his sys em is based on (1) obse a ion o he exis ence o
di e se iso o ms o AGT and enin (as a esul o glycosyla ion and al e na i e splicing, espec i ely)
and di e en o ms o ACE (in acellula and sec e ed), (2) he exis ence o al e na i e enzymes o
he syn hesis o Ang II (such as ca hepsin and chymase), and (3) in acellula de ec ion o hese
componen s unde pa icula cellula condi ions. In addi ion, hese componen s mus be able o
media e biological e ec s om an in acellula loca ion o be unc ionally ele an [
15
]. In ac , changes
in cell s uc u e and gene ansc ip ion ha e been epo ed o induce he mobiliza ion o in acellula
calcium deposi s and s imula e he g ow h o di e en cell ypes ha e been epo ed [
13
,
15
]. In spi e o
ha , he unc ional oles o he in acellula RAS in physiology and pa hophysiology ha e no ye been
ully elucida ed.
Axes ha Compose he RAS
Nowadays, RAS has been desc ibed as a complex sys em composed by he canonical axis as well as
he non-canonical axes (Figu e 1), whose componen s a e widely exp essed in all cell ypes and o gans
in humans. The e o e, RAS plays impo an oles in nume ous physiological e en s, such as enal,
neu onal, ca diac, panc ea ic, ascula , ad enal, pi ui a y, cogni i e, ageing- ela ed, in lamma o y and
ep oduc i e p ocesses [
16
]. No ably, one o he mos ele an unc ions o he RAS is i s pa icipa ion
in a ious p ocesses ela ed o male e ili y [7,8,17,18].
In . J. Mol. Sci. 2020,21, 7943 4 o 18
Renin/ACE/Ang II/AT1R/AT2R axis is a well-known pa hway as i is conside ed he canonical o
sys ema ic pa hway, which is mainly o med by AGT; enin; ACE; Ang I and Ang II and hei ecep o s,
AT1R and AT2R. Angio ensin III (angio ensin (2–8) o Ang III) is p oduced om Ang II h ough he
ac ion o he enzyme aminopep idase A (APA) and exe s i s ac ions h ough AT1R and AT2R [
6
,
10
].
T adi ionally, he main unc ions o his axis we e conside ed o be he main enance o BP and elec oly e
and luid homeos asis. O he unc ions ha e since been a ibu ed o he axis a he local and in acellula
le els, which di e depending on he ecep o ha igge s he signal [
6
,
15
]. AT1R is de ini i ely
known o ope a e h ough a ious signalling mechanisms, such as by inc easing he in acellula
le els o Ca
2+
(by inc easing he in lux o ex acellula Ca
2+
and he mobiliza ion o in acellula Ca
2+
);
ac i a ing a ious kinase pa hways, including he mi ogen-ac i a ed p o ein (MAP) kinase pa hway;
and ac i a ing he epide mal g ow h ac o ecep o (EGFR) in he plasma memb ane. In con as ,
he e ec s o AT2R s imula ion a e media ed mainly by phospha ases [
19
]. The e o e, he e ec s o
AT2R- and AT1R-media ed signalling ha e been conside ed o be an agonis ic [
6
,
10
,
19
]. AT1R has hus
been associa ed wi h physiological esponses such as asocons ic ion, he in lamma o y esponse,
cell p oli e a ion o oxida i e s ess, while AT2R has been associa ed wi h p ocesses such as asodila ion;
apop osis; and an i-in lamma ion, an i-cell p oli e a ion and an i-oxida i e s ess p ocesses [19].
The p o eolysis cascade o ACE2/Ang(1–7)/MasR non-canonical axis s a s wi h ACE2. This enzyme
clea es Ang II o di ec ly gene a e Ang (1–7), which exe s i s ac ion by binding o MasR. Addi ionally,
Ang I can be clea ed by many o he pep idases, especially neu al endopep idase (NEP), which can
gene a e Ang (1–7). Finally, his hep apep ide can also be gene a ed ia he hyd olysis o Ang I by
ACE2 o o m angio ensin (1–9) (Ang (1–9)), which is subsequen ly clea ed by NEP o ACE. Howe e ,
i is impo an o highligh ha his pa hway seems o be ca aly ically less e icien han he ones
men ioned abo e [
20
]. Di e en s udies ha e obse ed an agonis ic e ec s be ween he p o eins Ang II
and Ang (1–7) as well as among he ecep o s on which hey ac , he G-p o ein coupled ecep o s
(GPCRs) MasR and AT1R [
7
]. Indeed, he bene icial e ec s o his axis encompass a ious biological
p ocesses, such as asodila ion and he s imula ion o b adykinin and NO elease [20].
The Ang IV/AT4R-IRAP axis is ano he non-canonical axis. In his signalling pa hway, Ang III is
ans o med in o angio ensin (3–8), also called angio ensin IV (Ang IV), by he ac ion o aminopep idase
N (APN) and aminopep idase B (APB). Ang IV ul ima ely ac s h ough binding o AT4R/IRAP [
21
].
This axis plays key oles in he egula ion o cogni i e unc ions such as lea ning and memo y,
enal me abolism, ca dio ascula damage, modula ion o glucose up ake in o cells, and egula ion o
he g ow h o se e al cell ypes [13].
Finally, he (p o) enin/PRR axis has been desc ibed a e disco e y o he exis ence o he enin
ecep o (PRR) [
12
], which ac s independen ly o he classical axis a e ac i a ion by enin i sel
and i s p ecu so , (p o) enin [
12
,
22
] and i has been linked o ca dio ascula , enal and degene a i e
diseases [22].
3. The RAS and Male Fe ili y
The es ablishmen o male e ili y comp ises a se ies o in ica e and highly s uc u ed s eps ha
depend on complex o ches a ion o communica ion sys ems, especially he RAS. In ac , nume ous
componen s o his sys em ha e been desc ibed in many o gans and issues o he male ep oduc i e
ac , including he epididymis [
23
,
24
], as de e ens [
25
], p os a e [
26
], seminal luid [
27
–
29
], es es [
9
,
30
],
and spe ma ozoa [
8
,
31
–
33
]. In addi ion, accumula ing da a om
in i o
, animal and clinical s udies ha e
indica ed ha his pep ide sys em is in ol ed in he co ec unc ioning o he human male ep oduc i e
sys em and is equen ly al e ed o de egula ed in pa hological condi ions [8,18,22,29,31–33].
In . J. Mol. Sci. 2020,21, 7943 5 o 18
3.1. Regula ion o Tes icula Func ion by Local RAS
The main unc ions o he es es a e he o ma ion o spe ma ozoa, o spe ma ogenesis, and he
p oduc ion o es os e one, o s e oidogenesis. Conside ing he impo ance and complexi y o hese
p ocesses, i is easy o unde s and he s ic endoc ine, pa ac ine and au oc ine egula ion o which
hey mus be subjec and how hei de egula ion can con ibu e o male in e ili y [
4
,
5
]. The i s poin
o ho monal egula ion o es icula unc ion is he hypo halamic-pi ui a y- es icula axis [
5
]. Se e al
membe s o he RAS a e p esen in he es es, such as enin and Ang II, and a e egula ed by sex
ho mones as well as by gonado opins [
30
,
34
] (Figu e 2). Likewise, a ious pa ac ine and au oc ine
mechanisms modula e es icula unc ion a he local le el by ac ing on di e en ypes o cells p esen
in his issue, such as Se oli, Leydig and/o spe ma ogenic cells [
4
]. A his poin , he local RAS
becomes in ol ed; his RAS is isola ed om he plasma RAS by a es icula blood ba ie ha p o ec s
male e ili y om subs ances such as AT1R blocke s and ACE inhibi o s [
22
]. Wi hin his local sys em,
nume ous esea che s ha e ound e idence o he syn hesis and p esence o componen s o di e en
axes o he RAS.
In .J.Mol.Sci.2020,21,xFORPEERREVIEW5o 18
p ocesses,i iseasy ounde s and hes ic endoc ine,pa ac ineandau oc ine egula ion owhich
heymus besubjec andhow hei de egula ioncancon ibu e omalein e ili y[4,5].The i s poin 
o ho monal egula iono  es icula  unc ionis hehypo halamic‐pi ui a y‐ es icula axis[5].Se e al
membe so  heRASa ep esen in he es es,suchas eninandAngII,anda e egula edbysex
ho monesaswellasbygonado opins[30,34](Figu e2).Likewise, a iouspa ac ineandau oc ine
mechanismsmodula e es icula  unc iona  helocalle elbyac ingondi e en  ypeso cellsp esen 
in his issue,suchasSe oli,Leydigand/o spe ma ogeniccells[4].A  hispoin , helocalRAS
becomesin ol ed; hisRASisisola ed om heplasmaRASbya es icula bloodba ie  ha p o ec s
male e ili y omsubs ancessuchasAT1Rblocke sandACEinhibi o s[22].Wi hin hislocal
sys em,nume ous esea che sha e ounde idenceo  hesyn hesisandp esenceo componen so 
di e en axeso  heRAS.

Figu e2.Endoc ine egula iono  he es icula RAS.A  he es icula le el,a e gonado opin
s imula ion, hele elso AngIIand enininc ease,while heexp essiono  hegenesencodingbo h
AngII ecep o saswellas hele elso  he ecep o sdec ease.On heo he hand,a e 
hypophysec omy, hele elso  enindec ease,bu  hemRNAexp essiono AT1RandAT2R
inc eases.A  hecellula le el,inLeydigcells,exogenousadminis a iono gonado opinsinc eases
hele elso AngIandIIand enin,whe easoes ogen ea men o hypophysec omydec eases enin
le els.
3.1.1.TheRenin/ACE/AngII/AT1R/AT2RAxis
Allmembe so  hisaxisha ebeen oundin he es eso  a iousmammals,includinghumans
(Table1).Theini ials udiesca iedou in his ega dshowed ha  hemajo elemen so  hisaxis,
AGT[34]and enin[35–37],a ep esen inLeydigcells.A  i s i was hough  ha  hesep o eins
o igina edin hesys emicRAS,since he es icula le elso AGTand eninandsubsequen lyACE,
AngIIandi s ecep o sinc easea  hebeginningo pube ywi h heappea anceo LHandFSHin
hebloods eam[8,38,39].La e ,i wasobse ed ha  hei  ansc ip sa esyn hesizedinLeydigcells
[6,34,40],indica ing hei localp oduc ionand helinked egula ionbe ween hesys emicandlocal
RAS[22].Inaddi ion,i hasbeen ound ha inc easesin eninle elscauseinc easesin es os e one
syn hesis[38];howe e , u he s udiesa enecessa y oelucida ewhe he suchinc easesin
es os e onea edue odi ec ac ionon hePRRo signalling h ough hecanonicalpa hway.
Figu e 2.
Endoc ine egula ion o he es icula RAS. A he es icula le el, a e gonado opin
s imula ion, he le els o Ang II and enin inc ease, while he exp ession o he genes encoding bo h
Ang II ecep o s as well as he le els o he ecep o s dec ease. On he o he hand, a e hypophysec omy,
he le els o enin dec ease, bu he mRNA exp ession o AT1R and AT2R inc eases. A he cellula
le el, in Leydig cells, exogenous adminis a ion o gonado opins inc eases he le els o Ang I and II
and enin, whe eas oes ogen ea men o hypophysec omy dec eases enin le els.
3.1.1. The Renin/ACE/Ang II/AT1R/AT2R Axis
All membe s o his axis ha e been ound in he es es o a ious mammals, including humans
(Table 1). The ini ial s udies ca ied ou in his ega d showed ha he majo elemen s o his axis,
AGT [
34
] and enin [
35
–
37
], a e p esen in Leydig cells. A i s i was hough ha hese p o eins
o igina ed in he sys emic RAS, since he es icula le els o AGT and enin and subsequen ly ACE,
Ang II and i s ecep o s inc ease a he beginning o pube y wi h he appea ance o LH and FSH

In . J. Mol. Sci. 2020,21, 7943 6 o 18
in he bloods eam [
8
,
38
,
39
]. La e , i was obse ed ha hei ansc ip s a e syn hesized in Leydig
cells [
6
,
34
,
40
], indica ing hei local p oduc ion and he linked egula ion be ween he sys emic
and local RAS [
22
]. In addi ion, i has been ound ha inc eases in enin le els cause inc eases in
es os e one syn hesis [
38
]; howe e , u he s udies a e necessa y o elucida e whe he such inc eases
in es os e one a e due o di ec ac ion on he PRR o signalling h ough he canonical pa hway.
Likewise, Ang I has also been ound in he es es, mainly in Leydig cells [
41
], se ing as a subs a e
o ACE. In ac , he es es also con ain much highe concen a ions o ACE (also known as ACE1)
han o he o gans [
6
,
42
]. In e es ingly, in he es es, wo iso o ms o his enzyme, soma ic ACE
(sACE) and es icula o ge minal ACE ( ACE o gACE), ha e been obse ed. E en hough bo h
a e ansc ibed om he same gene, hey di e s uc u ally by he p esence/absence o a 66-amino
acid sequence [
43
] and consequen ly p esen di e en molecula s uc u es. sACE is o med by wo
iden ical subuni s, whe eas ACE is o med by a single subuni [
44
–
47
] and bo h exhibi compa able
enzyma ic ac i i y [
6
]. The ansc ip ion o he es icula o m is issue-speci ic and occu s as a esul
o al e na i e splicing, al e na i e ansc ip ion ini ia ion, and al e na i e polyadenyla ion [
9
,
48
,
49
].
The mos no able di e ences be ween he iso o ms a e hei loca ions; while ACE is p esen only in
male ge m cells [
9
,
50
,
51
], being ound in high concen a ions du ing spe miogenesis [
6
,
9
], sACE is
exp essed in o he es icula cells, such as Leydig cells and endo helial cells o he es icula in e s i ial
issue [
9
], and in a soluble o m in seminal plasma [
42
]. Al hough he concen a ion o sACE in he
es es is among he highes in all o gans he speci ic ole o sACE in he es es emains unknown.
sACE-de icien mice a e e ile and he es es migh be he sou ces o his enzyme in seminal luid [
6
],
whe e i p o ec s spe m du ing and a e ans e o emales [52].
The Ang II pep ide is p esen in bo h ge m cells [
35
] and in Leydig cells [
41
]. The p esence o a
blood- es icula ba ie , oge he wi h he ac ha all he componen s necessa y o he p oduc ion o
his p o ein ( enin, ACE, AGT and Ang I) a e ound wi hin Leydig cells, suppo s he in acellula
syn hesis o his pep ide. Ang II has been epo ed o be capable o inhibi ing adenyla e cyclase
ac i i y in a Leydig cells, educing basal and gonado opin-s imula ed cAMP and es os e one
p oduc ion [
53
,
54
]. On he o he hand, i has also been p oposed ha Ang II may play a ole in
es icula g ow h and/o di e en ia ion [
55
]. Finally, he Ang II ecep o s AT1R and AT2R ha e also
been de ec ed in a , monkey and human es es, speci ically in Leydig cells [
53
,
56
,
57
]. Howe e ,
he p o ein le els o bo h ecep o s, as well as he le els o hei espec i e mRNAs, depend on age;
o example, he exp ession o AT2R p edomina es in he i s days o li e bu g adually dec eases
un il he ou h week o li e, lea ing AT1R o be almos exclusi ely exp essed [
40
]. I is unknown
whe he hese ecep o s play a ole in he egula ion o es icula o ma ion [
6
]. No ably, wo sub ypes
o AT1R, AT1AR and AT1BR, ha e been desc ibed in he es es o mice bu no in hose o humans,
al hough no speci ic unc ions ha e been es ablished o ei he o hese sub ypes [
21
]. The p esence o
AT1R has also been obse ed in a and human semini e ous ubules, speci ically in spe m cells a
di e en ma u a ion s ages (spe ma ogonia and spe ma ids), sugges ing ha his ecep o could be
in ol ed in spe ma ogenesis [
57
]. Finally, Ang II, h ough i s binding o AT1R, may in e e e wi h
es os e one p oduc ion [55].
Addi ional s udies ha e shown ha Ang II is ans o med in o Ang III by he ac ion o APA,
a e which Ang III exe s i s ac ion by binding o AT1R and AT2R [
6
,
10
]. The APA enzyme has been
de ec ed in a es is homogena es, showing high enzyma ic ac i i y. I has been p oposed ha his
enzyme, like Ang II, is in ol ed in inhibi ing s e oidogenesis h ough p oduc ion o Ang III and
ac i a ion o AT1R [58].
Taken oge he , hese indings a i m ha his canonical axis modula es s e oidogenesis. Speci ically,
Ang II and III, h ough binding o AT1R, nega i ely egula e es os e one p oduc ion. Mo eo e ,
AT1R may be in ol ed in he spe ma ogenesis p ocess. Al hough u u e s udies a e necessa y, i has
been sugges ed a posi i e egula ion o s e oidogenesis h ough he AT2R, conside ing he con as ing
e ec s o AT1R and AT2R.
In . J. Mol. Sci. 2020,21, 7943 7 o 18
Table 1. Regula ion o he es icula unc ion by local RAS.
Axis Componen Func ion Re e ences
Renin/ACE/Ang II/
AT1R/AT2R axis
AGT Local p oduc ion o Ang II
Dzau e al. 1987, Spe h e al. 1999
ACE Local p oduc ion o Ang II -
Ang II
Nega i e egula ion o
es os e one p oduc ion
Regula ion o es icula
g ow h and/o
di e en ia ion
Du au e al. 1989,
Khanum and Du au 1988
Schunke e al. 1993;
Leung and Se nia 2003
Hi ai e al. 1998
Ang III Nega i e egula ion o
es os e one p oduc ion
de la Chica-Rod iguez e al. 2008,
Ma inez-Ma os e al. 2011
AT1R
Nega i e egula ion o
spe ma ogenesis and
es os e one p oduc ion
Vinson e al. 1995
Hi ai e al. 1998
APA Nega i e egula ion o
es os e one p oduc ion de la Chica-Rod iguez e al. 2008
ACE2/Ang (1–7)/
MasR axis
ACE2
Posi i e egula ion o
spe ma ogenesis
Posi i e egula ion o
es os e one p oduc ion
Reis e al. 2010
Pan e al. 2013
Ang-(1–7)
Posi i e egula ion o
es os e one p oduc ion
Posi i e egula ion
o spe ma ogenesis
Alenina e al. 2002,
Leal e al. 2009, Xu e al. 2007
Reis e al. 2010
MasR
Posi i e egula ion o
spe ma ogenesis
Regula ion o
es os e one p oduc ion
Reis e al. 2010
NEP
Regula ion o spe m
ma u a ion and
p oac osin ac i a ion
E dos e al., 1985
Ang IV
AT4R-IRAP axis
Ang IV Nega i e egula ion o
es os e one p oduc ion
de la Chica-Rod iguez e al. 2008,
Ma inez-Ma os e al. 2011
APN
Al e a ion o Se oli
cells unc ion
Nega i e egula ion o
spe ma ogenesis and
es os e one p oduc ion
Osada e al. 2001
Ma inez-Ma os e al. 2011
APB Nega i e egula ion o
es os e one p oduc ion Ma inez-Ma os e al. 2011
(P o) enin/
PRR axis
(P o) enin Posi i e egula ion o
spe ma ogenesis Mukhopadhyay e al. 1995
Renin Posi i e egula ion o
es os e one p oduc ion Pa men ie e al. 1983
3.1.2. The ACE2/Ang (1–7)/MasR Axis
All he p incipal componen s o he axis ACE2/Ang (1–7)/MasR ha e been de ec ed in a , mouse,
and human es es [
32
]. Single-cell RNA sequencing da a on human es es showed p edominan
exp ession o ACE2 in spe ma ogonia, Leydig and Se oli cells [
59
], bu ACE2 has been ound o be
localized only in Leydig cells a he p o ein le el [
60
,
61
]. Al hough Ace2-null mice a e e ile [
62
],
men wi h se e ely impai ed spe ma ogenesis ha e lowe le els o ACE2 han e ile men, sugges ing
ha his enzyme may modula e spe m o ma ion [
32
]. ACE2 has also been epo ed o play key oles
In . J. Mol. Sci. 2020,21, 7943 8 o 18
in he egula ion o es os e one p oduc ion and in he local ascula egula o y sys em, in which i
balances in e s i ial luid olume by modula ing he con e sion o Ang II o Ang I [
52
]. Ang (1–7) has
also been iden i ied and cha ac e ized in mouse [
61
,
63
], a [
63
] and human es es [
32
], in he cy oplasm
o Leydig cells, and in Se oli cells and p ima y spe ma ocy es a lowe le els [
32
]. This hep apep ide
is in ol ed in he egula ion o spe ma ogenesis, since lowe le els o Ang-(1–7) ha e been ound
in men wi h se e e spe ma ogenesis impai men han in e ile men [
32
]. Simila o his pep ide,
MasR has been desc ibed o be p esen in he cy oplasm o mouse [
60
,
63
], human Leydig cells
and inside he human semini e ous ubules in all laye s o he no mal semini e ous epi helium,
being equally dis ibu ed be ween in e s i ial and ubula compa men s [
32
]. Howe e , i s mRNA
has been de ec ed in bo h Leydig and Se oli cells, wi h i s exp ession being mo e p onounced in he
la e , bu no in de eloping ge m cells [
60
]. Conce ning MasR unc ion, MasR-de icien mice ha e
cons i u i e al e a ions in he ac i i y o genes encoding s e oidogenic enzymes wi hin he es es [
60
,
64
].
This inding and he obse a ion ha MasR and Ang-(1–7) a e p esen in Leydig cells, sugges ha
bo h MasR and Ang-(1–7) could play a key ole in modula ing he p oduc ion o es os e one [
32
].
No ably, i has been epo ed ha MasR-de icien mice show ma ked educ ions in es is weigh ,
a signi ican inc ease o apop o ic cells du ing meiosis, he p esence o gian cells and acuoles in
he semini e ous epi helium, and s iking educ ions in daily spe m p oduc ion due o dis u bed
spe ma ogenesis [
63
,
65
], al hough he o al numbe s o Se oli and Leydig cells a e compa able in bo h
wild- ype and knockou animals [
65
]. Mo eo e , MasR le els a e no ably dec eased o absen unde
condi ions o se e e spe ma ogenesis al e a ion in humans, p o iding insigh s in o he ole o he MasR
in he egula ion o spe ma ogenesis [32].
Al hough he e a e no da a in he li e a u e ha speci ically show he p esence o Ang (1–9)
in he es es, he p esence o Ang I and Ang (1–7), as well as he enzymes ACE, ACE2 and NEP,
could indica e ha his pep ide is p esen in his issue [
6
,
7
]. On he o he hand, NEP has been de ec ed
in human es es [
66
] and in he memb anes o a Se oli cells [
67
], and i s ac i i y is low in es icula
homogena e [
66
] bu high in Se oli cells [
67
]. I has been sugges ed ha his me alloendopep idase
may be ela ed o spe m ma u a ion and p oac osin ac i a ion [
66
]. Ne e heless, NEP-de icien mice
ha e no mal es icula unc ion [
68
]. Simila ly, an iso o m o his enzyme, NEP2, has been obse ed in
mouse [
69
] and human es es [
70
]. S udies ha e also demons a ed he p esence o NEP2 mRNA in he
semini e ous ubules, speci ically in de eloping ge m cells and mainly in spe ma ids [
71
]. Howe e ,
he conc e e unc ion o NEP2 in he es es emains unknown.
Taken oge he , hese da a clea ly indica e ha his axis plays key oles in egula ing s e oidogenesis
and spe ma ogenesis (Table 1).
3.1.3. The Ang IV/AT4R-IRAP Axis
This pa hway begins wi h he ac ion o APN o APB. The me allopep idase APN has been
localized in bo h human [
72
] and mouse es es, showing high gene exp ession in Se oli and Leydig
cells [
73
]. APN seems o play a ole in he inhibi ion o es os e one syn hesis [
74
]. In ac , mice lacking
APN p esen de ec s in spe ma ogenesis and in e ili y, as hey ha e al e ed Se oli cell unc ion [
73
].
In addi ion, APB has been de ec ed in mouse es es, and i also pa icipa es in inhibi ion o he syn hesis
o his ho mone [74] (Table 1).
Al hough he speci ic unc ion o Ang IV in he es es emains unknown, Ang IV could also be
in ol ed in inhibi ion o es icula es os e one p oduc ion [
58
,
74
]. Likewise, al hough he p esence o
AT4R/IRAP in he es es has no ye been desc ibed, he p esence o he o he componen s o his axis
could indica e ha his ecep o is p esen in his issue. Despi e he sca ci y o e idence ega ding he
p esence and unc ions o he main membe s o Ang IV/AT4R-IRAP axis in he es es, he a ailable
da a show how his axis is also ela ed o inhibi ion o es icula es os e one p oduc ion and, he e o e,
in he egula ion o spe ma ogenesis.
In . J. Mol. Sci. 2020,21, 7943 9 o 18
3.1.4. The (P o) enin/PRR Axis
P o enin is known o be p oduced and sec e ed by he es es [
75
] and i has been ound a co ela ion
be ween spe m densi y and he p o enin le el in semen [
76
]. Simila ly, i has been shown ha Leydig
cells a e capable o p oducing enin [
6
,
34
,
40
] and ha enin le els a e di ec ly ela ed o es icula
es os e one concen a ions [
38
]. Thus, i could be hypo hesized ha his axis is posi i ely in ol ed in
s e oidogenesis (Table 1). None heless, as p e iously desc ibed, he (p o) enin/PRR axis was desc ibed
a e he exis ence o he PRR was disco e ed [
12
]. No e idence has ye been epo ed showing ha his
ecep o is p esen in he es es; he e o e, u he s udies should be pe o med in o de o demons a e
he p esence o PRR and consequen ly he exis ence o his axis as well as o unde s and he unc ional
ole o p o enin and/o enin independen o he e ec s o he classical RAS cascade.
3.2. Regula ion o Spe m Phisiology by Local RAS
In o de o acqui e e iliza ion abili y, spe ma ozoa mus unde go a se ies o p ocesses,
such as mo ili y acquisi ion; capaci a ion; he ac osomal eac ion; and oocy e ecogni ion, usion
and ac i a ion [
77
]. These p ocesses mus be pe ec ly egula ed o ensu e p ope de elopmen . I is
known ha igh con ol is exe ed by he join ac ions o complex biological sys ems, including he
RAS [
21
,
40
,
77
]. Accumula ed e idence ega ding he p esence, dis ibu ions and speci ic unc ions
o di e en membe s o his pep ide sys em in spe m cells sugges s ha he RAS egula es male
ep oduc i e unc ion by ac ing di ec ly on he e ili y po en ial o spe ma ozoa [
8
]. In addi ion, as has
been obse ed o es icula unc ion, he di e en RAS axes could exe opposi e oles, which would
esul in ine modula ion o ep oduc i e unc ion (Table 2).
Table 2. Regula ion o he spe m physiology by local RAS.
Axis Componen Func ion Re e ences
Renin/ACE/Ang II/
AT1R/AT2R axis
AGT In ol ed in
spe m-oocy e usion Temp e e al. 2000
ACE
Regula ion o spe m
mo ili y, capaci a ion,
ac osome eac ion and
spe m-oocy e usion
In ol ed in emb yo
quali y and de elopmen
Siems e al. 1991,
Yamaguchi e al. 2006,
Fo es a e al. 1987, Kohn e al. 1995,
Hagaman e al. 1998,
K ege e al. 1995
, Fo es a e al. 1991,
Gianzo e al. 2018,
Gianzo e al. 2018
ACE3 In ol ed in
spe m-oocy e usion Inoue e al. 2010
Ang II
Regula ion o spe m
mo ili y, capaci a ion and
ac osome eac ion
Fo es a e al. 1991, Kohn e al. 1995,
Sabeu e al. 2000, Vinson e al. 1996,
Wennemu h e al. 1999
AT1R Regula ion o
spe m mo ili y Vinson e al. 1996
AT2R Regula ion o
spe m mo ili y Gianzo e al., 2016
ACE2/Ang (1–7)/
MasR axis
Ang-(1–7) Posi i e egula ion o
spe m mo ili y Valdi ia e al. 2020
MasR Regula ion o
spe m mo ili y Valdi ia e al. 2020
NEP Nega i e egula ion o
spe m mo ili y Subi an e al. 2008
NEP2
Nega i e in ol ed in
oocy e e iliza ion and
emb yo de elopmen
Regula ion o
spe m mo ili y
Ca pen ie e al. 2004
Pin o e al. 2010
In . J. Mol. Sci. 2020,21, 7943 16 o 18
64.
Xu, P.; San os, R.A.; Bade , M.; Alenina, N. Al e a ions in Gene Exp ession in he Tes is o Angio ensin-(1–7)-
Recep o Mas-De icien Mice. Regul. Pep . 2007,138, 51–55. [C ossRe ] [PubMed]
65.
Wal he , T.; Balschun, D.; Voig , J.P.; Fink, H.; Zusch a e , W.; Bi chmeie , C.; Gan en, D.; Bade , M. Sus ained
Long-Te m Po en ia ion and Anxie y in Mice Lacking he Mas P o ooncogene. J. Biol. Chem.
1998
,273,
11867–11873. [C ossRe ] [PubMed]
66.
E dos, E.G.; Schulz, W.W.; Ga o d, J.T.; De endini, R. Neu al Me alloendopep idase in Human Male Geni al
T ac . Compa ison o Angio ensin I-Con e ing Enzyme. Lab. In es ig. J. Tech. Me hods Pa hol.
1985
,52,
437–447.
67.
Monsees, T.K.; Go nig, M.; Schill, W.B.; Miska, W. Possible In ol emen o P o eases in he Regula ion o
Spe ma ogenesis. And ologia 1998,30, 185–191. [C ossRe ] [PubMed]
68.
Ca pen ie , M.; Guilleme e, C.; Bailey, J.L.; Boileau, G.; Jeanno e, L.; DesG oseille s, L.; Cha on, J. Reduced
Fe ili y in Male Mice De icien in he Zinc Me allopep idase NL1. Mol. Cell. Biol.
2004
,24, 4428–4437.
[C ossRe ] [PubMed]
69.
Ghadda , G.; Ruchon, A.F.; Ca pen ie , M.; Ma cinkiewicz, M.; Seidah, N.G.; C ine, P.; Desg oseille s, L.;
Boileau, G. Molecula Cloning and Biochemical Cha ac e iza ion o a New Mouse Tes is Soluble-Zinc-
Me allopep idase o he Nep ilysin Family. Biochem. J. 2000,347, 419–429. [C ossRe ]
70.
Bon ouloi , N.; Lemieux, N.; C ine, P.; Boileau, G.; DesG oseille s, L. Molecula Cloning, Tissue Dis ibu ion,
and Ch omosomal Localiza ion o MMEL2, a Gene Coding o a No el Human Membe o he Neu al
Endopep idase-24.11 Family. DNA Cell Biol. 2001,20, 493–498. [C ossRe ]
71.
Pin o, F.M.; Ra ina, C.G.; Subi an, N.; Cejudo-Roman, A.; Fe nandez-Sanchez, M.; I azus a, J.; Ga ido, N.;
Candenas, L. Au oc ine Regula ion o Human Spe m Mo ili y by Tachykinins. Rep od. Biol. Endoc inol.
2010
,
8, 104. [C ossRe ]
72.
Huang, K.; Takaha a, S.; Kinouchi, T.; Takeyama, M.; Ishida, T.; Ueyama, H.; Nishi, K.; Ohkubo, I. Alanyl
Aminopep idase om Human Seminal Plasma: Pu i ica ion, Cha ac e iza ion, and Immunohis ochemical
Localiza ion in he Male Geni al T ac . J. Biochem. 1997,122, 779–787. [C ossRe ]
73.
Osada, T.; Wa anabe, G.; Kondo, S.; Toyoda, M.; Sakaki, Y.; Takeuchi, T. Male Rep oduc i e De ec s Caused
by Pu omycin-Sensi i e Aminopep idase De iciency in Mice. Mol. Endoc inol.
2001
,15, 960–971. [C ossRe ]
74.
Ma inez-Ma os, J.M.; A azola, M.; Mayas, M.D.; Ca e a-Gonzalez, M.P.; Ga cia, M.J.; Rami ez-Exposi o, M.J.
Die -Induced Hype choles e olemia Impai ed Tes icula S e oidogenesis in Mice h ough he Renin-
Angio ensin Sys em. Gen. Comp. Endoc inol. 2011,173, 15–19. [C ossRe ]
75.
Sealey, J.E.; Golds ein, M.; Pi a esi, T.; Kudlak, T.T.; Glo ioso, N.; Fiamengo, S.A.; La agh, J.H. P o enin
Sec e ion om Human Tes is: No E idence o Sec e ion o Ac i e Renin o Angio ensinogen. J. Clin.
Endoc inol. Me ab. 1988,66, 974–978. [C ossRe ] [PubMed]
76.
Mukhopadhyay, A.K.; Cobilanschi, J.; Schulze, W.; B unswig-Spickenheie , B.; Leidenbe ge , F.A. Human
Seminal Fluid Con ains Signi ican Quan i ies o P o enin: I s Co ela ion wi h he Spe m Densi y. Mol. Cell.
Endoc inol. 1995,109, 219–224. [C ossRe ]
77.
Yoshida, M.; Kawano, N.; Yoshida, K. Con ol o Spe m Mo ili y and Fe ili y: Di e se Fac o s and Common
Mechanisms. Cell Mol. Li e Sci. 2008,65, 3446–3457. [C ossRe ] [PubMed]
78.
C a en, D.J.; Wa en, A.Y.; Symonds, E.M. Ac i e and Inac i e Renin in Human Seminal Plasma. A ch. And ol.
1981,7, 63–67. [C ossRe ]
79.
Hohlb ugge , G.; Pscho , J.; Dahlheim, H. Angio ensin I Con e ing Enzyme in he Ejacula e o Fe ile and
In e ile Men. Fe il. S e il. 1984,41, 324–325. [C ossRe ]
80.
Temp e , C.B.; Mo eno, R.M.; G egg, A.R. Gene ic Con ol o Fe ili y and Emb yonic Was e in he Mouse:
A Role o Angio ensinogen. Biol. Rep od. 2000,62, 457–462. [C ossRe ]
81.
Vanha-Pe ula, T.; Ma he , J.P.; Ba din, C.W.; Moss, S.B.; Bell e, A.R. Localiza ion o he An igo ensin-
Con e ing Enzyme Ac i i y in Tes is and Epididymis. Biol. Rep od.
1985
,33, 870–877. [C ossRe ] [PubMed]
82.
B en jens, J.R.; Ma suo, S.; And es, G.A.; Caldwell, P.R.; Zamboni, L. Game es Con ain Angio ensin
Con e ing Enzyme (Kininase II). Expe ien ia 1986,42, 399–402. [C ossRe ]
83.
Dob inski, I.; Igno z, G.G.; Fagnan, M.S.; Yudin, S.I.; Ball, B.A. Isola ion and Cha ac e iza ion o a P o ein
wi h Homology o Angio ensin Con e ing Enzyme om he Pe iac osomal Plasma Memb ane o Equine
Spe ma ozoa. Mol. Rep od. De . 1997,48, 251–260. [C ossRe ]

In . J. Mol. Sci. 2020,21, 7943 17 o 18
84.
Ganong, W.F. Rep oduc ion and he Renin-Angio ensin Sys em. Neu osci. Biobeha . Re .
1995
,19, 241–250.
[C ossRe ]
85.
Kohn, F.M.; Dammshause , I.; Neukamm, C.; Rennebe g, H.; Siems, W.E.; Schill, W.B.; Aumulle , G.
Ul as uc u al Localiza ion o Angio ensin-Con e ing Enzyme in Ejacula ed Human Spe ma ozoa.
Hum. Rep od. 1998,13, 604–610. [C ossRe ] [PubMed]
86.
Singh, U.S.; Kuma , M.V.; Panda, J.N. Angio ensin Con e ing Enzyme in Semen and i s Possible Role in
Capaci a ion. And ologia 1985,17, 472–475. [C ossRe ] [PubMed]
87.
Fo es a, C.; Indino, M.; Manoni, F.; Scandella i, C. Angio ensin-Con e ing Enzyme Con en o Human
Spe ma ozoa and i s Release du ing Capaci a ion. Fe il. S e il. 1987,47, 1000–1003. [C ossRe ]
88.
Fo es a, C.; Mioni, R.; Rossa o, M.; Va o o, A.; Zo zi, M. E idence o he In ol emen o Spe m Angio ensin
Con e ing Enzyme in Fe iliza ion. In . J. And ol. 1991,14, 333–339. [C ossRe ]
89.
Kohn, F.M.; Miska, W.; Schill, W.B. Release o Angio ensin-Con e ing Enzyme (ACE) om Human
Spe ma ozoa du ing Capaci a ion and Ac osome Reac ion. J. And ol. 1995,16, 259–265.
90.
Shibaha a, H.; Kama a, M.; Hu, J.; Nakagawa, H.; Oba a, H.; Kondoh, N.; Shima, H.; Sa o, I. Ac i i y o Tes is
Angio ensin Con e ing Enzyme (ACE) in Ejacula ed Human Spe ma ozoa. In . J. And ol.
2001
,24, 295–299.
[C ossRe ]
91.
Siems, W.E.; Hede , G.; Hilse, H.; Baege , I.; Engel, S.; Jen zsch, K.D. Angio ensin-Con e ing Enzyme and
O he Pep idoly ic Enzymes in Human Semen and Rela ions o i s Spe ma ologic Pa ame e s. And ologia
1991,23, 185–189. [C ossRe ]
92.
Yamaguchi, R.; Yamaga a, K.; Ikawa, M.; Moss, S.B.; Okabe, M. Abe an Dis ibu ion o ADAM3 in Spe m
om bo h Angio ensin-Con e ing Enzyme (Ace)—and Calmegin (Clgn)-De icien Mice. Biol. Rep od.
2006
,
75, 760–766. [C ossRe ]
93.
Gianzo, M.; U iza -A enaza, I.; Munoa-Hoyos, I.; La ea egui, Z.; Ga ido, N.; Casis, L.; I azus a, J.;
Subi an, N. Human Spe m Tes icula Angio ensin-Con e ing Enzyme Helps De e mine Human Emb yo
Quali y. Asian J. And ol. 2018,20, 498–504. [PubMed]
94.
K ege, J.H.; John, S.W.; Langenbach, L.L.; Hodgin, J.B.; Hagaman, J.R.; Bachman, E.S.; Jenne e, J.C.;
O’B ien, D.A.; Smi hies, O. Male-Female Di e ences in Fe ili y and Blood P essu e in ACE-De icien Mice.
Na u e 1995,375, 146–148. [C ossRe ] [PubMed]
95.
Hagaman, J.R.; Moye , J.S.; Bachman, E.S.; Sibony, M.; Magya , P.L.; Welch, J.E.; Smi hies, O.; K ege, J.H.;
O’B ien, D.A. Angio ensin-Con e ing Enzyme and Male Fe ili y. P oc. Na l. Acad. Sci. USA
1998
,95,
2552–2557. [C ossRe ] [PubMed]
96.
Inoue, N.; Kasaha a, T.; Ikawa, M.; Okabe, M. Iden i ica ion and Dis up ion o Spe m-Speci ic Angio ensin
Con e ing Enzyme-3 (ACE3) in Mouse. PLoS ONE 2010,5, e10301. [C ossRe ]
97.
Vinson, G.P.; Meh a, J.; E ans, S.; Ma hews, S.; Pudde oo , J.R.; Sa idogan, E.; Hol , W.V.; Djahanbakhch, O.
Angio ensin II S imula es Spe m Mo ili y. Regul. Pep . 1996,67, 131–135. [C ossRe ]
98.
Wennemu h, G.; Babcock, D.F.; Hille, B. Dis ibu ion and Func ion o Angio ensin II Recep o s in Mouse
Spe ma ozoa. And ologia 1999,31, 323–325.
99.
Sabeu , K.; Vo, A.T.; Ball, B.A. E ec s o Angio ensin II on he Ac osome Reac ion in Equine Spe ma ozoa.
J. Rep od. Fe il. 2000,120, 135–142. [C ossRe ]
100.
Vinson, G.P.; Pudde oo , J.R.; Ho, M.M.; Ba ke , S.; Meh a, J.; Sa idogan, E.; Djahanbakhch, O. Type 1
Angio ensin II Recep o s in Ra and Human Spe m. J. Endoc inol. 1995,144, 369–378. [C ossRe ]
101.
Gu , Y.; B ei ba , H.; Lax, Y.; Rubins ein, S.; Zami , N. Angio ensin II Induces Ac osomal Exocy osis in
Bo ine Spe ma ozoa. Am. J. Physiol. 1998,275, E87–E93. [C ossRe ]
102.
Valdi ia, A.; Co
é
s, L.; Bei ia, M.; To o ikaguena, L.; Agi egoi ia, N.; Co cos egui, B.; Casis, L.; Ma o as, R.;
I azus a, J.; Agi egoi ia, E. Role o Angio ensin-(1–7) Via MAS Recep o in Human Spe m Mo ili y and
Ac osome Reac ion. Rep oduc ion 2020,159, 241–249. [C ossRe ]
103.
Subi an, N.; Agi egoi ia, E.; Valdi ia, A.; Ochoa, C.; Casis, L.; I azus a, J. Exp ession o Enkephalin-Deg ading
Enzymes in Human Semen and Implica ions o Spe m Mo ili y. Fe il. S e il.
2008
,89, 1571–1577. [C ossRe ]
104.
Togo, T.; Mo isawa, M. Aminopep idase-Like P o ease Released om Oocy es A ec s Oocy e Su aces and
Supp esses he Ac osome Reac ion in Es ablishmen o Polyspe my Block in Oocy es o he Mussel My ilus
Edulis. De . Biol. 1997,182, 219–227. [C ossRe ] [PubMed]
105.
Togo, T.; Mo isawa, M. GPI-Ancho ed Aminopep idase is In ol ed in he Ac osome Reac ion in Spe m o
he Mussel My ilusedulis. Mol. Rep od. De . 2004,67, 465–471. [C ossRe ] [PubMed]
In . J. Mol. Sci. 2020,21, 7943 18 o 18
106.
Kha un, A.; Rahman, M.S.; Ryu, D.Y.; Kwon, W.S.; Pang, M.G. Ele a ed Aminopep idase N A ec s Spe m
Mo ili y and Ea ly Emb yo De elopmen . PLoS ONE 2017,12, e0184294. [C ossRe ] [PubMed]
107.
Kha un, A.; Kang, K.H.; Ryu, D.Y.; Rahman, M.S.; Kwon, W.S.; Pang, M.G. E ec o Aminopep idase N
on Func ions and Fe ili y o Mouse Spe ma ozoa in Vi o. The iogenology
2018
,118, 182–189. [C ossRe ]
[PubMed]
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