Am J Physiol Renal Physiol 320: F243–F248, 2021.

First published January 19, 2021; doi:10.1152/ajprenal.00601.2020

PERSPECTIVES

Androgens, the kidney, and COVID-19: an opportunity for translational research

Licy L. Yanes Cardozo,1,2,3,4,5 Samar Rezq,1,3,4,5 Jacob E. Pruett,1,3,4,5 and Damian G. Romero1,3,4,5
1
Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi; 2Department of
Medicine, University of Mississippi Medical Center, Jackson, Mississippi; 3Mississippi Center for Excellence in Perinatal
Research, University of Mississippi Medical Center, Jackson, Mississippi; 4Women’s Health Research Center, University of
Mississippi Medical Center, Jackson, Mississippi; and 5Cardio Renal Research Center, University of Mississippi Medical
Center, Jackson, Mississippi

Abstract
Coronavirus disease 2019 (COVID-19) has reached pandemic proportions, affecting millions of people worldwide. Severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19. Epidemiological reports have shown that
the severity of SARS-CoV-2 infection is associated with preexisting comorbidities such as hypertension, diabetes mellitus, cardio-
vascular diseases, and chronic kidney diseases, all of which are also risk factors for acute kidney injury (AKI). The kidney has
emerged as a key organ affected by SARS-CoV-2. AKI is associated with increased morbidity and mortality in patients with
COVID-19. Male sex is an independent predictor for AKI, and an increased death rate has been reported in male patients with
COVID-19 worldwide. The mechanism(s) that mediate the sex discrepancy in mortality due to COVID-19 remain(s) unknown.
Angiotensin-converting enzyme (ACE)2 is the receptor for SARS-CoV-2. Alterations in the ACE-to-ACE2 ratio have been impli-
cated in renal diseases. This perspective aims to discuss data that suggest that androgens, via alterations in the intrarenal renin-
angiotensin system, impair renal hemodynamics, predisposing patients to AKI during COVID-19 infection, which could explain the
higher mortality observed in men with COVID-19. Clinicians should ensure early and effective cardiometabolic control for all
patients to ameliorate the compensatory elevation of ACE2 and alterations in the ACE-to-ACE2 ratio. A better understanding of
the role of androgens in SARS-CoV-2-associated AKI and mortality is imperative. The kidney could constitute a key organ that
may explain the sex disparities of the higher mortality and worst outcomes associated with COVID-19 in men.

androgens; COVID-19; kidney; renin-angiotensin system; SARS-CoV-2

INTRODUCTION rate has been reported in males compared with females

Coronavirus disease 2019 (COVID-19) has reached pan-
demic proportions, affecting more than 50 million people
and causing more than 1.2 million deaths worldwide (1).
Severe acute respiratory syndrome coronavirus-2 (SARS-
CoV-2) is the causative agent of the COVID-19 pandemic.
Early epidemiological reports have shown that the severity
of SARS-CoV-2 infection is frequently associated with preex-
isting comorbidities such as hypertension, diabetes mellitus,
cardiovascular diseases, and chronic kidney diseases (2), all
of which are also risk factors for acute kidney injury (AKI)
(3). Among the several organs affected by SARS-CoV-2, the
kidney has emerged as a key one (4). AKI is defined as a re-
versible decline in the glomerular filtration rate (GFR) that
results in the accumulation of waste products (5). AKI is
associated with increased morbidity and mortality in
patients with COVID-19 (6–9) and is more likely to occur in
patients with elevated basal serum creatinine (7). AKI is also
a risk factor for chronic kidney disease (10). Recent studies
have shown that male sex is an independent predictor for
AKI in patients with COVID-19 (8, 11, 12). An increased death
worldwide (13, 14). Although still unclear, there are multiple
plausible hypotheses for this sex discrepancy in mortality
due to COVID-19. Some of the plausible explanations could
be: 1) male sex is a risk factor per se; 2) COVID-19-associated
comorbidities have a higher prevalence in males compa-
red with females, before SARS-CoV-2 infection; 3) female
patients with COVID-19 have more robust T-cell activation
than male patients (15); or 4) male patients with COVID-19
have an increased prevalence of neutralizing autoantibodies
against type I interferons than their female counterparts
(16). This perspective aims to discuss data from experimental
models that suggest that androgens via alterations in
the intrarenal renin-angiotensin-aldosterone system (RAAS)
impair renal hemodynamics, predisposing patients to AKI
during COVID-19 infection, which could explain the higher
mortality observed in men.
ANDROGENS, THE KIDNEY, AND COVID-19
The androgens testosterone and its most potent metabo-
lite, dihydrotestosterone (DHT), bind to the androgen

Correspondence: L. L. Yanes Cardozo (lyanes@umc.edu); D. G. Romero (dromero@umc.edu).

Submitted 9 November 2020 / Revised 17 December 2020 / Accepted 13 January 2021

http://www.ajprenal.org 1931-857X/21 Copyright © 2021 the American Physiological Society F243

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 ANDROGENS, THE KIDNEY, AND COVID-19
receptor (AR) to elicit an androgenic response. In the kidney,
AR is highly expressed in proximal tubule cells (17), glomeru-
lar endothelial cells (18), and podocytes (19). Podocyte dam-
age is a hallmark of renal injury and associated proteinuria
(20). SARS-CoV-2 viral particles have been identified in glo-
meruli and more specifically in podocytes during SARS-CoV-
2 infection (21, 22). Furthermore, SARS-CoV-2 viral particles
have been isolated from autopsied kidneys and were able to
replicate in cell culture (23). All these data strongly indicate
that not only SARS-CoV-2 RNA, protein, and viral particles
are found in human kidneys but also viable infective viral
particles. Moreover, postmortem analysis of SARS-CoV-2-
positive patients has showed that those in which SARS-CoV-
2 RNA could be detected in the kidney present a reduction in
survival time, supporting a positive association between
SARS-CoV-2 renal infection and COVID-19 disease severity
(23). Data from experimental animal models have shown
that GFR is lower in females compared with males, due to
higher renal vascular resistance in females. Thereby, the
male kidney is vasodilated compared with the female kidney
(24). Renal hyperfiltration is thought to be a key initiating
factor in renal injury in patients with diabetes mellitus and
obesity (25, 26). It has been hypothesized that renal hyperfil-
tration is an indication of generalized endothelial dysfunc-
tion (27). Afferent arterioles are resistance vessels in the
kidney, which play a major role in regulating both the myo-
genic response and tubuloglomerular feedback. Those two
are critical mechanisms for renal protection during insults
(28). It has been recently demonstrated that testosterone via
AR dilates norepinephrine-preconstricted mouse afferent
arterioles in a dose-dependent manner (29) and also enhan-
ces tubuloglomerular feedback (30). Thereby, it could be
hypothesized that androgen-mediated vasodilation of the
afferent arteriole enhances the transmission of systemic
pressure to the glomerulus, resulting in increases in intraglo-
merular pressure that finally lead to renal injury, which may
be subclinical in many instances. Furthermore, androgens
can increase efferent arteriolar resistance, by increasing re-
nal angiotensin II (ANG II) levels, leading to an exacerbation
of glomerular injury (31). Androgens are inversely associated
with renal function in apparently healthy men without a his-
tory of cardiovascular disease (32). Moreover, testosterone
has been reported to increase thromboxane A2 receptor den-
sity and responsiveness in rat aortas (33), a prostanoid that
plays a potential role in the development of microvascular
dysfunction (34). During the COVID-19 clinical course, there
is generalized microvascular dysfunction (35), which could
lead to renal hypoperfusion in the presence of androgen-
mediated renal injury, resulting in AKI. Supporting this hy-
pothesis, recent studies have shown that the most frequent
finding in patients with AKI and COVID-19 is acute tubular
necrosis (36–38) but, in another study, glomerular injury was
reported (39). Recent studies have suggested that androge-
netic alopecia, a clinical indicator of androgen excess bio-
logical activity, is present in an elevated proportion of hospi-
talized patients with COVID-19 (40) and also correlates with
worsening respiratory status and death in patients with
COVID-19 (41). Randomized controlled clinical trials testing
the AR blocker bicalutamide (NCT04374279), the gonadotro-
pin release hormone antagonist degarelix (NCT04397718), and
the mineralocorticoid receptor and AR blocker spironolactone
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(NCT04345887) in patients with COVID-19 are currently under-
way. Whether AR blockers will decrease the mortality and
prevalence of AKI in COVID-19 is unclear at present.
POLYCYSTIC OVARIAN SYNDROME,
TRANSGENDER INDIVIDUALS, AND COVID-19
Polycystic ovarian syndrome (PCOS) is the most common
endocrine disorder in reproductive-age women with a preva-
lence of 5%–20% in this population (42, 43). PCOS is charac-
terized by clinical and/or biochemical signs of hyperan-
drogenism, oligo- or anovulation, and/or polycystic ovaries.
Hyperandrogenism is present in more than 80% of women
with PCOS and those women have a worse metabolic profile
than normoandrogenic subjects with PCOS (43–47). Import-
antly, microvascular endothelial dysfunction is observed
in women with PCOS and is driven by androgens (48).
Moreover, serum testosterone positively correlates with
markers of renal injury in patients with PCOS (49). Whether
women with PCOS are prone to higher SARS-CoV-2 death
rates, AKI, or long-term renal deleterious consequences due
to COVID-19 is currently unknown but highly plausible. We
have previously established an animal model of PCOS in
female rats that mimics many of the metabolic and cardio-
vascular abnormalities observed in women with PCOS (50).
Chronic administration of DHT to female rats causes an
increase in food intake, obesity, insulin resistance, blood
pressure, GFR, and renal hyperfiltration, as observed in
women with PCOS (50–53). More research is needed to deter-
mine whether women with PCOS infected with SARS-CoV-2
have a higher prevalence of AKI and mortality compared
with normal cycling women. Transgender men are persons
who, due to their sexual secondary characteristics at birth,
are assigned a female gender but identify themselves as
males. Testosterone is used to stop menses and induce virili-
zation, including a male pattern of sexual and facial hair, a
change in voice, male body physical appearance, and tes-
tosterone levels similar to cisgender males. A recent publi-
cation showed that transgender men had increased
endothelial dysfunction compared with cisgender women
(54). Whether the presence of endothelial dysfunction in
this population is associated with renal hemodynamic
changes is unknown. It can be hypothesized that COVID-
19 infection is associated with worsened morbidity and
mortality in transgender men.
THE RAAS, ACE2, AND COVID-19
What could be the mechanism(s) that underline the abnor-
mal androgen-mediated renal hemodynamics? The RAAS is
a major regulator of blood pressure and it is composed of
classical and nonclassical arms with opposite effects on renal
physiology. In the classical RAAS arm, angiotensinogen is
cleaved by circulating renin to generate angiotensin I, which,
in turn, is converted to ANG II by angiotensin-converting
enzyme (ACE). ANG II binds and activates the ANG II type 1
receptor (AT1R) to increase blood pressure, sodium reabsor-
ption, and renal vasoconstriction. We and others have
shown that androgens upregulate intrarenal angiotensino-
gen expression (55, 56). In the nonclassical RAAS arm, the
membrane-bound carboxypeptidase enzyme ACE2 converts
 ANDROGENS, THE KIDNEY, AND COVID-19
ANG II to angiotensin 1–7 (ANG 1–7). ANG 1–7 binds to the
Mas receptor, opposing most of the (patho)physiological
actions of ANG II in the kidney.
ACE2 is highly expressed in the kidney (57). ACE2 is the re-
ceptor for the coronavirus that causes COVID-19, SARS-CoV-
2 (58). ACE2 is highly expressed in proximal tubule cells;
however, recent single-cell transcriptome studies have
shown that ACE2 is also expressed in glomerular epithelial
cells and podocytes (59, 60). Moreover, AR regulates the
transcription of TMPRSS2 (61), a required protease for SARS-
CoV-2 entry into target cells that is coexpressed in those
same cell types (59, 60). Although SARS-CoV2 enters cells
through membrane-bound ACE2, there is also concern that
it will downregulate ACE2 as SARS-CoV does (62, 63), which
could lead to an increased ACE-to-ACE2 ratio. An elevated
ACE-to-ACE2 ratio has been implicated in several renal dis-
eases (63, 64). Plasma ACE2 activity is low in healthy subjects
but elevated in patients with cardiovascular disease or renal
diseases, especially in men (65–67). The increased plasma
ACE2 activity in males (65–67) could be due to increased
ACE2 expression or decreased a disintegrin and metallopro-
teinase 17 (ADAM17) activity; ADAM17 cleaves membrane-
bound ACE2 to generate soluble (circulating) ACE2. ADAM17
expression has been reported to be decreased by androgens in
LNCaP prostate cancer cell (68), which would result in
decreased soluble ACE2 levels. Whether ADAM17 is subject to
the same regulation by androgens in normal tissues is
unknown and could help to understand sex differences in
Androgens
Kidney
Dilatation
Afferent
arteriole
ANG II
Constriction
Efferent ANG II
arteriole
Increased intraglomerular
pressure and glomerular injury
COVID-19-associated Acute Kidney Injury
Figure 1. Physiological, cellular, and molecular mechanisms by which androgens lead to COVID-19-associated acute kidney injury in severe acute respi-
ratory syndrome coronavirus-2 (SARS-CoV-2) infection. ACE2, angiotensin-converting enzyme 2; ANG II, angiotensin II.
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COVID-19 outcomes. Moreover, it is possible to speculate that
the increase in renal ACE2 could represent a compensatory
mechanism to endothelial dysfunction in response to several
insults. More research needs to be done to demonstrate the
direct effect of androgen upon intrarenal and extrarenal ACE-
to-ACE2 ratios before and during COVID-19 infection.
A meta-analysis of more than 1.2 million subjects with pre-
viously normal estimated GFR (eGFR) showed that those
with hypertension have an increased risk of developing AKI
(69). Recent studies have highlighted the key role of ACE2 in
mediating sexual dimorphism in blood pressure control (70).
Ji et al. (70) showed using an elegant set of experiments that
male mice have a faster increase in ANG II-induced increase
in blood pressure than female mice and that ACE2 genetic
ablation increased the rate of ANG II-induced hypertension
in female mice with a negligible effect on male mice. Those
studies supported the notion of a larger protective effect of
ACE2 in female mice than in male mice. Interestingly, the
ACE2 gene is located on the X chromosome (71), which raises
the possibility that differences in sex chromosome dosage
(2X vs. 1X) could impact ACE2 activity. The Four Core
Genotypes rodent model allows dissecting the gonadal
effects from sex chromosome effects. Recently, Liu et al. (72)
reported that renal ACE2 activity, using optimized enzy-
matic conditions, and expression are higher in male mouse
kidneys compared with female mouse kidneys. Moreover, es-
tradiol reduced renal ACE2 activity, and the effect of estra-
diol was independent of sex and the sex chromosomal
Epithelial cells
Tubular cells
Podocytes
ACE2
SARS-CoV-2
Viral entry and replication
ACE2
ACE2 Tubular Microvascular
downregulation injury Dysfunction
F245
 ANDROGENS, THE KIDNEY, AND COVID-19
complement (72). In the same study, gonadectomy did not
affect the expression or activity of ACE2 in male kidneys
(72). We have previously reported that some of the renal
actions of androgen excess in female rats persisted for
months after androgen withdrawal (51); whether this is also
the case in male mice is unknown. All these data highlight
plenty of opportunities for further research to fully elucidate
the role of sex steroids on ACE2 expression and activity
regulation.
RAAS blockers such as ACE inhibitors or AT1R blockers are
drug classes widely used to treat hypertension. ACE2 shares
considerable homology with ACE but is not inhibited by ACE
inhibitors. The recent report showing that ACE2 functions as
the receptor for SARS-CoV-2 stirred unprecedented contro-
versy in the field on the continuous use of RAAS blockers in
patients who tested positive for COVID-19 as well as at-risk
populations. RAAS blockers increase systemic and tissue
ACE2 expression and activity in preclinical models (73, 74).
However, there is no evidence to support an association
between RAAS blockers use and more severe disease; some
large studies and a systematic review found no relationship
between the use of these drugs and severity of COVID-19 (75),
whereas other data suggest that these drugs may actually
attenuate the severity of disease (76, 77). Interestingly, men
with hypertension are treated more frequently with RAAS
blockers, whereas diuretics are more frequently prescribed in
women (78). This difference in drug prescription is presum-
ably due to RAAS blockers’ potential teratogenic effects (79).
The role that RAAS blockers play in the prevalence of AKI and
mortality in patients with COVID-19 is unclear at present.
Figure 1 shows the proposed physiological, cellular, and
molecular mechanisms by which androgens lead to COVID-
19-associated AKI in SARS-CoV-2 infection.
CONCLUSIONS
At present, there is no cure for COVID-19, defining cure as
the reversion of all affected organs and systems by SARS-CoV-2
to the predisease state (80–82). Clinicians need to ensure early
and effective cardiometabolic control for all patients to amelio-
rate the compensatory elevation of ACE2 and alterations in the
ACE-to-ACE2 ratio. A better understanding of the role of andro-
gens underlying the mortality and acute renal injury associated
with SARS-CoV-2 infection is imperative. The kidney could
constitute a key organ that may explain the sex disparities of
the higher mortality associated with COVID-19 in men.
GRANTS
This work was supported by National Institutes of Health
Grants P20GM121334 (to L.L.Y.C. and D.G.R.) and R21DK113500
(to D.G.R.).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by
the authors.
DISCLAIMERS
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institutes of Health.
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AUTHOR CONTRIBUTIONS
L.L.Y.C., S.R., J.E.P., and D.G.R. drafted manuscript; L.L.Y.C., S.
R., J.E.P., and D.G.R. edited and revised manuscript; L.L.Y.C., S.R.,
J.E.P., and D.G.R. approved final version of manuscript.
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