Impact of Aging and Cellular Senescence in the Pathophysiology of Preeclampsia.

The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive disorder of pregnancy, has been associated with an increased risk of future disease, including cardiovascular and kidney diseases. Cellular senescence, the process of cell cycle arrest in response to many physiologic and maladaptive stimuli, may play an important role in the pathogenesis of preeclampsia and provide a mechanistic link to future disease. In this article, we will discuss the pathophysiology of preeclampsia, the many mechanisms of cellular senescence, evidence for the involvement of senescence in the development of preeclampsia, as well as evidence that cellular senescence may link preeclampsia to the risk of future disease. Lastly, we will explore how a better understanding of the role of cellular senescence in preeclampsia may lead to therapeutic trials. © 2023 American Physiological Society. Compr Physiol 13:5077-5114, 2023.

Obesity-associated cardiometabolic complications in polycystic ovary syndrome: The potential role of sodium-glucose cotransporter-2 inhibitors.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by androgen excess, oligo/anovulation, and polycystic appearance of the ovaries. Women with PCOS have an increased prevalence of multiple cardiovascular risk factors such as insulin resistance, hypertension, renal injury, and obesity. Unfortunately, there is a lack of effective, evidence-based pharmacotherapeutics to target these cardiometabolic complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors provide cardiovascular protection in patients with and without type 2 diabetes mellitus. Although the exact mechanisms of how SGLT2 inhibitors confer cardiovascular protection remains unclear, numerous mechanistic hypotheses for this protection include modulation of the renin-angiotensin system and/or the sympathetic nervous system and improvement in mitochondrial function. Data from recent clinical trials and basic research show a potential role for SGLT2 inhibitors in treating obesity-associated cardiometabolic complications in PCOS. This narrative review discusses the mechanisms of the beneficial effect of SGLT2 inhibitors in cardiometabolic diseases in PCOS.

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition.

BACKGROUND: Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium-glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model. METHODS: Four-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study. RESULTS: PCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups. CONCLUSIONS: Hyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model.

Sodium-Glucose Cotransporter-2 Inhibition Benefits in Cardiorenal Risk in Men and Women.

Introduction: In addition to their antihyperglycemic action, sodium-glucose cotransporter-2 (SGLT2) inhibitors are used in patients with type 2 diabetes due to their cardioprotective effects. Meta-analyses of large clinical trials have reported mixed results when examining sex differences in their cardioprotective effects. For example, some studies reported that, compared to women, men had a greater reduction in cardiovascular risk with SGLT2 inhibition. Taking advantage of several recently completed large-scale randomized controlled clinical trials, we tested the hypothesis that women have an attenuated response in primary cardiorenal outcomes to SGLT2 inhibition compared to men. Methods: We performed a systematic search using PubMed and the Cochrane Library to find completed large-scale, prospective, randomized controlled Phase III clinical trials with primary outcomes testing cardiovascular or renal benefit. Studies had to include at least 1000 participants and report data about sex differences in their primary cardiovascular or renal outcomes. Results: The present meta-analysis confirmed that SGLT2 inhibition decreased adverse cardiorenal outcomes in a pooled sex analysis using 13 large-scale clinical trials. SGLT2 inhibition exhibited similar reduction in hazard ratios for both men (0.79, 95% CI, 0.73-0.85) and women (0.78, 95% CI, 0.72-0.84) for adverse cardiorenal outcomes. Conclusion: In contrast to previous findings, our updated meta-analysis suggests that women and men experience similar cardiorenal benefit in response to SGLT2 inhibition. These findings strongly suggest that SGLT2 inhibition therapy should be considered in patients with high risk for cardiovascular disease irrespective of the patient sex.

Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.

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

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.