Effect of Angiotensin‐converting Enzyme Inhibition on Systemic and Renal RAS Components in a Hyperandrogenemic Rat Model of PCOS

Abstract

Polycystic Ovary Syndrome (PCOS) is characterized by androgen excess, oligo/anovulation, and polycystic ovaries. Obesity, insulin resistance (IR) and increased blood pressure (BP) are associated with PCOS. Therapeutic options for PCOS are limited and the mechanisms responsible for the cardiometabolic complications seen in PCOS are uncertain. It is unclear if androgen‐mediated increases in BP contribute to obesity and/or IR in PCOS. The renin angiotensin system (RAS), a regulator of BP, is affected by androgens and is associated with increased BP in PCOS. To investigate the role of androgens and the contribution of the RAS in PCOS, RAS inhibition via an angiotensin‐converting enzyme inhibitor (ACEi) was performed in a PCOS‐like rat model. We hypothesized that ACEi would attenuate obesity and IR in PCOS. Female SD rats (4 week old) received dihydrotestosterone (DHT, 7.5 mg/ 90 days) pellets (HAF) subcutaneously or sham surgeries (CON). The rats were then assigned tap water or tap water with the ACEi, enalapril (ENA) (250mg/L) for n=10/group. At the end of the study (16 week old) body weight (BW), body composition by EchoMRI, and IR by HOMA‐IR were assessed. Renal RAS gene expression was assessed by qPCR. BP was measured by radiotelemetry and plasma and renal ACE and ACE2 activities were assessed. HAF had increased BW, fat mass and IR vs CON. ENA reduced BW in only HAF. Overall, ENA decreased fat mass, and the decrease in HAF neared significance. ENA did not attenuate IR in HAF. In HAF, angiotensinogen (Agt) mRNA was increased in the renal cortex and medulla, while ACE and angiotensin II receptor type 1a (Atr1a) mRNA was increased in the medulla vs CON. In HAF, ENA had no impact on renal Agt, ACE or Atr1a mRNA. ACE2 mRNA was increased in the medulla of HAF vs CON, and ENA increased medulla ACE2 mRNA in both HAF and CON. HAF had increased BP, and ENA decreased BP in both HAF and CON by a similar degree. Overall, ENA decreased plasma ACE activity but only increased plasma ACE2 activity in HAF. ENA increased cortical ACE2 activity in both HAF and CON. In summary, ACEi therapy in a PCOS model reduced BW, BP and adiposity but had no impact on IR. Renal classic RAS gene expression is upregulated in the HAF but unchanged by ENA. Furthermore, only ACE2 mRNA expression was altered in the HAF with ENA. In addition, the expression of other RAS component genes that were unchanged by ACEi in HAF were significantly impacted by ACEi in CON. This reveals a complex interaction between androgen exposure and renal RAS component gene expression. Increased BP in the HAF did not correlate with plasma or renal ACE or ACE2 activities. Chronic RAS inhibition may be a promising therapeutic approach for androgen‐mediated increases in BP and obesity in AE‐PCOS, though additional therapy would be needed for IR.