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

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, cardiovascular 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 implicated 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.

INTRODUCTION

Coronavirus disease 2019 (COVID-19) has reached pandemic 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 preexisting 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 reversible 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 rate has been reported in males compared with females 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 compared 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 metabolite, dihydrotestosterone (DHT), bind to the androgen receptor (AR) to elicit an androgenic response. In the kidney, AR is highly expressed in proximal tubule cells (17), glomerular endothelial cells (18), and podocytes (19). Podocyte damage is a hallmark of renal injury and associated proteinuria (20). SARS-CoV-2 viral particles have been identified in glomeruli 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 hyperfiltration is an indication of generalized endothelial dysfunction (27). Afferent arterioles are resistance vessels in the kidney, which play a major role in regulating both the myogenic 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 enhances 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 intraglomerular pressure that finally lead to renal injury, which may be subclinical in many instances. Furthermore, androgens can increase efferent arteriolar resistance, by increasing renal 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 history of cardiovascular disease (32). Moreover, testosterone has been reported to increase thromboxane A₂ receptor density 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 hypothesis, 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 androgenetic alopecia, a clinical indicator of androgen excess biological activity, is present in an elevated proportion of hospitalized 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 gonadotropin release hormone antagonist degarelix (NCT04397718), and the mineralocorticoid receptor and AR blocker spironolactone (NCT04345887) in patients with COVID-19 are currently underway. 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 prevalence of 5%–20% in this population (42, 43). PCOS is characterized by clinical and/or biochemical signs of hyperandrogenism, 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). Importantly, 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 cardiovascular 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 determine 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 virilization, including a male pattern of sexual and facial hair, a change in voice, male body physical appearance, and testosterone levels similar to cisgender males. A recent publication 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 abnormal 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 reabsorption, and renal vasoconstriction. We and others have shown that androgens upregulate intrarenal angiotensinogen expression (55, 56). In the nonclassical RAAS arm, the membrane-bound carboxypeptidase enzyme ACE2 converts 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 receptor 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 diseases (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 metalloproteinase 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 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 previously 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 enzymatic conditions, and expression are higher in male mouse kidneys compared with female mouse kidneys. Moreover, estradiol reduced renal ACE2 activity, and the effect of estradiol was independent of sex and the sex chromosomal 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 controversy 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 presumably 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.

Figure 1.

Physiological, cellular, and molecular mechanisms by which androgens lead to COVID-19-associated acute kidney injury in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. ACE2, angiotensin-converting enzyme 2; ANG II, angiotensin II.

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 ameliorate the compensatory elevation of ACE2 and alterations in the ACE-to-ACE2 ratio. A better understanding of the role of androgens 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.

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.