Androgens and Diet Regulation of SARS‐CoV‐2 Viral Entry Proteins: Implications for COVID‐19 Cardiorenal Outcomes Severity in Polycystic Ovary Syndrome

Abstract

Background The susceptibility and the severity of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) are associated with hyperandrogenism, obesity, and pre‐existing pulmonary, metabolic, renal or cardiac conditions. Hyperandrogenemia and ovarian dysfunction characterize polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women. Women with PCOS have higher prevalence of obesity and higher incidence of cardiovascular diseases and renal injury, making them a population at risk for severe COVID‐19 outcomes. Methods Three‐week‐old female mice were implanted with Silastic tubes filled with the nonaromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle (empty tubes). Animals were maintained on high‐fat diet (HFD; 60% kcal fat) or low‐fat diet (LFD; 10% kcal fat, sucrose‐matched) for 90 days. Fat mass (EchoMRI), kidney and left ventricle (LV) weights as well as the cardiac and renal expression of the inflammatory markers interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and interleukin‐1β (IL‐1β) were assessed. Moreover, circulatory, urinary, renal and cardiac levels of SARS‐CoV‐2 host cell receptor angiotensin converting enzyme 2 (ACE2) were quantified. Additionally, renal and cardiac mRNA and protein expression of the multiple cellular proteases required for viral entry (TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) were assessed. Results HFD exacerbated DHT‐mediated increases in fat mass (20.28 ± 1.10 vs. 6.78 ± 0.43 g, p<0.05), kidney weight (33.79 ± 1.35 vs. 26.52 ± 1.08 g, p<0.05), LV hypertrophy (7.48 ± 0.21 vs. 6.41 ± 0.28 g, p<0.05) and renal and cardiac expression of the inflammatory marker IL‐6 (1.5 and 2.5‐fold, respectively). PCOS mice on both diets showed higher urinary ACE2 (LFD: 18‐fold, HFD: 10‐fold) and altered renal mRNA and/or protein expression of all the measured targets. DHT upregulated renal TMPRSS2 (1.19 ± 0.04 vs. 0.98 ± 0.03 AU, p<0.05) and cathepsin L (2.64 ± 0.25 vs. 0.62 ± 0.25 AU, p<0.05) proteins in HFD‐fed DHT‐treated mice compared to LFD‐fed DHT‐treated mice. In the heart, LFD‐fed DHT‐treated mice showed no change in ACE2 and the cellular proteases on either the mRNA or protein levels except for ADAM17 protein that was significantly upregulated (1.63‐fold) compared to the vehicle‐treated group. On the other hand, while HFD‐fed DHT‐treated mice showed similar increase in cardiac ADAM17 protein (1.64‐fold vs. LFD‐fed vehicle‐treated), they showed higher mRNA expression of ACE2 (1.83‐fold) and furin (1.32‐fold) compared to the HFD‐fed vehicle‐treated mice. Conclusion and significance Our findings highlight women with PCOS as a population with a high risk of COVID‐19 associated cardiac and renal complications. Further, our study suggests dietary control recommendations for optimal management of women with PCOS that can ultimately attenuate COVID‐19 cardiorenal outcomes.