Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Mississippi Center of Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Int J Mol Sci. 2021 Mar 4;22(5):2576. doi: 10.3390/ijms22052576.
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.
多囊卵巢综合征（PCOS）是生殖年龄妇女最常见的内分泌疾病。PCOS 的特征是高雄激素血症和排卵功能障碍。患有 PCOS 的女性肥胖、胰岛素抵抗（IR）、血压升高（BP）和肾素血管紧张素系统（RAS）激活的患病率很高。缺乏有效的循证治疗方法来改善 PCOS 的心脏代谢并发症。钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂恩格列净（EMPA）可降低 2 型糖尿病患者的血压和高血糖。我们假设高雄激素血症上调肾脏 SGLT2 的表达，而 EMPA 可改善高雄激素血症 PCOS 模型的心脏代谢并发症。4 周龄雌性 Sprague Dawley 大鼠用二氢睾酮（DHT）处理 90 天，并在最后 3 周共同给予 EMPA。DHT 上调了肾脏 SGLT2、SGLT4 和 GLUT2，但下调了 SGLT3 mRNA 表达。EMPA 降低了 DHT 介导的脂肪量增加、血浆瘦素和 BP，但未能降低血浆胰岛素、HbA1c 或白蛋白尿。EMPA 降低了 DHT 介导的肾血管紧张素转换酶（ACE）、血管紧张素转换酶 2（ACE2）和血管紧张素 II 型 1 受体（AGT1R）mRNA 和蛋白表达。总之，SGLT2 抑制在高雄激素血症 PCOS 模型中证明对肥胖和血压降低有益；然而，可能需要额外的治疗方法来改善 IR 和肾脏损伤。
