Androgen Excess Promotes Hypertension and Cell-specific Renal Injury in Polycystic Ovary Syndrome: Protective Role of STAT3 Inhibition

Background: Women with Polycystic ovary syndrome (PCOS) frequently develop hypertension and renal injury, yet the underlying molecular mechanisms remain poorly understood. PCOS is characterized by chronic low-grade systemic inflammation and increased central adiposity that is associated with hyperleptinemia. The JAK/STAT3 pathway, activated by the inflammatory mediator interleukin-6 (IL-6) and adipokine leptin, enhances androgen receptor activity, driving oxidative stress and renal dysfunction. Although chronic JAK/STAT3 activation by androgens is well established in extra-renal tissues, its role in PCOS-associated renal injury is unknown. We aim to test the hypothesis that androgen excess activates JAK/STAT3 signaling via increasing IL-6 and leptin, leading to renal injury and hypertension, and that STAT3 inhibition mitigates these effects. Methods: Female rats (4-week-old) were implanted with dihydrotestosterone (DHT, 8 mg, 16 weeks, sc) to induce PCOS (n=4-7/gp). Rats received the JAK/STAT3 inhibitor Stattic (5 mg/kg, SC, 3x/week) or vehicle (Veh) for the last twelve weeks of DHT treatment. Urine was collected before and at 3- and 12-weeks post Stattic treatment. Blood pressure (BP) was assessed by radiotelemetry. Renal injury was assessed by kidney weight (Gravimetry), 24-hour proteinuria, and ROS production in kidney cortex and medulla (DCFH-DA fluorescence assay, kinetics). To assess cell-specific mechanisms across different renal tubule segments, murine proximal tubule (PT), thick ascending loop of Henle (TALH), and collecting duct (CD) cells were treated with DHT (10 nM, 24h) ± IL-6 (10 pg/ml) and leptin (20 ng/ml). Oxidative stress (DCFH-DA assay), cytotoxicity (LDH release), and viability (MTS assay) were quantified. Results: DHT increased proteinuria (1.5-fold) by 3 weeks. After 16 weeks, DHT increased kidney weight (3.1 ± 0.1 vs. 2.2 ± 0.2 g), mean arterial pressure (115 ± 2 vs. 108 ± 1 mmHg), and renal ROS. Stattic reduced kidney hypertrophy, decreased BP, and abolished DHT-induced increases in proteinuria, and renal ROS. In vitro, DHT induced ROS production in CD cells (50% increase), with no further enhancement by IL-6 or leptin. In TALH cells, DHT alone had no effect, whereas IL-6 and leptin independently increased oxidative stress (IL-6: 20% increase; leptin: 40% increase). In PT cells, DHT combined with IL-6 and leptin markedly potentiated oxidative stress compared to single or dual treatments. Stattic co-treatment abolished DHT-mediated oxidative stress in PT and CD cells but had minimal effects in TALH cells. It also decreased the release of the cytotoxicity marker LDH in PT cells. Cell viability was unchanged across treatments. Conclusion and Significance: Androgen excess promotes renal injury and hypertension in PCOS via STAT3 activation. Our data highlights cell-specific vulnerability across renal tubule segments, with proximal tubule and collecting duct cells being particularly sensitive to androgen-driven STAT3 activation, whereas thick ascending loop of Henle cells respond mainly to inflammatory mediators. These results identify STAT3 as a promising therapeutic target to mitigate renal injury in PCOS. Funding: NIH grants: P20GM121334 (SR, NSE, DGR), P30GM149404 (SR), and P50MD017338 (L.L.Y.C.); AHA grants: 25CDA1451435 (SR), 24PRE1200831 (JB), and 22CDA938320 (NSE); ADA grant: 1-26-PDF-0678 (ME); Additional support: 2024 Dean Franklin Award and 2025 Lazaro Mandel Award (NSE). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.