Diet-Androgen Interactions Drive Distinct Renal Injury Signatures in a Rat Model of Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) women are at increased risk of renal injury and hypertension (HTN). Obesity aggravates the cardiometabolic phenotype in PCOS. Consistently, we previously showed that western diet (WD) consumption by hyperandrogenemic female (HAF) rat (model of PCOS) causes exaggerated obesity and HTN. The present study tests the hypothesis that WD aggravates renal injury in PCOS via promoting renal mitochondrial dysfunction. Methods: Female SD rats (1 month) were implanted with either 5α-dihydrotestosterone (DHT, 7.5 mg/90 d, s.c.; HAF) or placebo (CON) pellet variable defined as androgens, and fed a control diet (CD) or WD (variable defined as diet) creating 4 groups (grps). At 6 months, we determined serum DHT and estradiol (LC/MS-MS), urinary proteins, creatinine, albumin and kidney injury molecule (KIM)-1, renal mitochondrial (mito.) complex I and II-driven respiration and fatty acid oxidation (FAO), and renal cortical superoxide dismutase (SOD)-1 (cytosolic), SOD2 (mitochondrial), catalase (CAT), and glutathione peroxidase (GPX1) mRNA levels by RT-qPCR, and SOD1, SOD2 and CAT activities (n=4-7). Results: Serum DHT increased significantly in both HAF grps compared to both CON grps (2.1-4.7-fold, p< 0.05). Urinary protein and albumin to creatinine ratios were significantly higher in HAF-CD and HAF-WD compared to CON-CD and CON-WD groups (p< 0.05). Both ratios and serum DHT levels were similar between HAF-CD and HAF-WD grps. KIM-1 was significantly higher only in HAF-WD compared to CON-CD grp (3-fold, p< 0.05). Serum estradiol, and renal mito complex I and II-driven respiration, and medium chain FAO were similar among the 4 grps. Interestingly, long chain FAO was significantly higher in HAF-WD grp compared to CON-CD, CON-WD and HAF-CD grps (~1.5-fold, p< 0.05). Renal mito. complex IV activity was higher in HAF-WD compared to HAF-CD (16.1±1.1 vs 7.4±0.2 nmol e-/nmol citrate, p< 0.05) and higher in both HAF grps compared to both CON grps (p< 0.05). Renal cortical SOD1, SOD2, CAT and GPX1 mRNA were significantly higher in HAF-CD compared to both CON grps (2-5-fold, p< 0.05), but were similar between HAF-WD and HAF-CD. Androgens (main variable) significantly increased renal cortical mito. SOD2 activity. Yet, renal cortical cytosolic SOD1 activity was lower in HAF-CD and HAF-WD compared to CON-CD and CON-WD grps (p< 0.05). CAT activity was higher in HAF-WD compared to CON-CD, CON-WD and HAF-CD grps (180±27 vs 100±15, 70±14 and 96±19 nmol/min/mg protein, p< 0.05, significant interaction between androgens and diet). Conclusion: WD consumption in HAF elicited distinct renal adaptations (enhanced mito. long chain FAO and complex IV activity), that may reflect metabolic compensation rather than direct injury drivers. Increased KIM-1, a sensitive marker of proximal tubular injury, and increased renal cytosolic catalase activity suggest diet-specific exacerbation of certain injury pathways in WD-fed HAF. Future studies will determine the diet-specific differential renal disease progression with aging in PCOS rat model. Funding: AHA-24DIVSUP1273026 (JA), NIH-NIGMS P20GM121334 (KE, NSE), AHA-22CDA938320, 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.