Targeting Renin Angiotensin System and Metabolic Outcomes in a Rat Model of Polycystic Ovary Syndrome: Role of Metformin
Authors: Abdelhameed Ahmed , Chatakondi Raksha , Rezq Samar , Everman Steven , Davenport Kacey , Vinson Ruth , Romero Damian , Yanes Cardozo Licy 
Published: May 2023

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is associated with high prevalence of insulin resistance (IR) and increases in blood pressure (BP). Activation of the Renin-Angiotensin System (RAS) is implicated in the pathophysiology of the elevated BP in PCOS. Metformin is the most common insulin sensitizer agent used to treat IR in PCOS women. Despite metformin’s ability to inhibit RAS overactivation in non-diabetic models, the potential of metformin to mitigate androgen-mediated RAS overactivation remains unknown. Aim and hypothesis: To test the hypothesis that metformin improves the metabolic abnormalities in PCOS via modulation of the intrarenal RAS. Methods: To induce PCOS, four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) pellets (7.5 mg) or placebo (PBO) for 90 days (n=6-10/group). During the final four weeks of DHT treatment, rats received metformin (300 mg/kg/day) in standard chow. Fat, lean mass and HOMA-IR, an index of insulin resistance (IR), were assessed. Plasma adiponectin and leptin levels were quantified by ELISA, while protein levels of angiotensin converting enzyme 2 (ACE2), renin, angiotensin type 2 receptor (AT2R), and angiotensinogen were quantified in the renal cortex by Western-blot. Results: DHT increased body weight (BW) (275.00 ± 8.20 vs 241.80 ± 2.95 g, p<0.05), kidney weight (2130 ± 49.17 vs 1468 ± 26.95 mg, p<0.05), fat mass (11.81 ± 1.84 vs 8.40 ± 0.96 g, p<0.05), and lean mass (253.00 ± 8.47 vs 214.74 ± 0.96 g, p<0.05), compared to PBO group. DHT significantly increased fasting plasma leptin and HOMA-IR (by 35 and 41%, respectively) while decreasing fasting plasma adiponectin level (by 33%) compared to PBO group. Interestingly, DHT significantly (p<0.05) upregulated renal cortical ACE2, AT2R, and angiotensinogen protein expression compared to the PBO group by 1.5-, 1.5- and 1.3- folds, respectively with no change in renin protein expression. Metformin treatment in PCOS rats had no impact on BW, kidney weight, fat mass, lean mass, plasma adiponectin or HOMA-IR, however it significantly decreased plasma leptin levels compared to PCOS rats treated with vehicle. Metformin also abolished DHT-mediated upregulation in ACE2, AT2R and angiotensinogen levels, while upregulating renal renin level by 1.5- fold compared to the vehicle-treated group. Conclusion: Our findings suggest that metformin can modulate intrarenal RAS components and improves leptin levels but it does not improve IR or body composition in PCOS model. Significance: Androgens in females cause IR which is associated with lower adiponectin levels. Changes in body composition, IR, and adiponectin levels in PCOS model are not improved by metformin. The intrarenal RAS system is a novel target for metformin in females with excess androgens. Targeting several pathways may be necessary to treat cardiometabolic complications in PCOS women. Supported by NIH-NIGMS grant P20GM121334 (L.L.Y.C. and D.G.R.), NIH-NIDDK grant R21DK113500 (D.G.R.), NIH-NIGMS grant P20GM121334, P20GM104357, NIH-NHLBI grant P01HL51971, and University of Mississippi Medical Center Medical Student Research Program (R.C.) and the Robert M. Hearin Foundation (R.C.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.