Role of the JAK/STAT3 Pathway in Obesity‐Induced Renal Injury in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in reproductive-age women, is characterized by oligo- or anovulation, hyperandrogenism, and polycystic ovaries. Both animal models and women with PCOS exhibit inflammation, obesity, and renal damage. The molecular mechanisms that mediate renal injury and dysfunction in PCOS, as well as its modulation by the diet are poorly understood. The JAK/STAT3 pathway, which is activated by interleukin-6 (IL-6) and leptin receptors, is involved in the pathophysiology of different models of renal injury. Despite its chronic activation in extra-renal tissues in PCOS and obesity models, the role of the JAK/STAT3 pathway in PCOS-mediated renal damage remains unknown. We aim to test the hypothesis that an obesogenic diet, via increased leptin and IL-6, activates the JAK/STAT3 signaling pathway to exacerbate androgen-induced renal injury.Three-week-old peripubertal female mice were implanted with Silastic tubes filled with the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle (empty tubes). Animals were fed either a high-fat diet (HFD; 60% kcal fat) or a low-fat diet (LFD; 10% kcal fat, sucrose-matched) for 90 days. Fat mass (EchoMRI), serum leptin (ELISA), kidney weight (gravimetry), and urinary albumin to creatinine ratio (UACR, clinical chemistry analyzer) were measured. Markers of renal inflammation [IL-6, tumor necrosis factor-α (TNF-α)], oxidative stress [NADPH oxidase2 (Nox2)], and fibrosis [collagen I, collagen III, transforming growth factor-β (TGF-β), and fibronectin] were quantified by RT-qPCR. Western blot analysis of active STAT3 [phosphorylated-STAT3 (Tyr705)] and total STAT3 proteins expression in the kidneys was also performed.In LFD-fed mice, DHT increased fat mass (20.28 ± 1.10 vs. 6.78 ± 0.43 g, p<0.05), serum leptin (1114.13 ± 133.68 vs. 299.27± 25.32 pg/mL, p<0.05), kidney weight (33.79 ± 1.35 vs. 26.52 ± 1.08 g, p<0.05) and UACR (1,227 ± 420 vs. 404 ± 169 μg albumin/g creatinine, p<0.05). DHT also increased the expression of renal inflammatory markers (TNF-α and IL-6). Notably, while DHT upregulated the expression of the fibrotic marker TGF-β in LFD-fed mice, it only induced the expression of Collagen I and Nox2 in the HFD-fed mice. Furthermore, HFD exacerbated DHT-mediated increases in adiposity and circulating leptin and IL-6, as well as renal inflammation, hypertrophy, and UACR. The disturbance in the aforementioned parameters was associated with increased renal STAT3 phosphorylation in HFD-fed DHT-treated mice compared to LFD- or HFD-fed controls (2.00- and 2.86-fold, respectively, p<0.05).Our findings suggest that diet-induced obesity plays a significant role in the renal outcomes in PCOS, and that increased STAT3 activation may explain the exacerbated renal injury in HFD-fed DHT-treated female mice. JAK/STAT3 pathway modulation could be novel therapeutic approach for diet-induced renal injury in PCOS. The implications of inhibiting specific STAT3 pathway components on the exacerbated renal impairment caused by obesity in our model of PCOS are currently being investigated.