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Role of JAK/STAT3 signaling in androgen-induced renal injury in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and presents with excess androgens and ovarian dysfunction. Increased androgen receptor (AR) signaling in PCOS is associated with renal injury and blood pressure (BP) increase. The molecular mechanisms underlying renal injury and dysfunction in PCOS are poorly understood. In a variety of animal renal injury models, the adipokine leptin and the inflammatory cytokine interleukin-6 (IL-6) activate the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway to exert renal injury. Despite its ability to directly activate AR, the role of JAK/STAT3 in excess androgen-mediated renal injury and its potential as therapeutic target in PCOS are unknown, and the focus of this proposal.

My preliminary data from a PCOS mouse model show that excess androgens [dihydrotestosterone (DHT), 8 mg, sc, 90 days] increased serum leptin, serum IL-6, and BP. DHT increased renal inflammation and fibrosis, increased AR levels, and activated STAT3 while decreasing glomerular filtration rate (GFR).

Excitingly, the selective STAT3 inhibitor Stattic (10 mg/kg, SC, three times/week, 90 days) attenuated DHT-induced increases in STAT3 activation and restored normal GFR values. My hypothesis is that, "In females, hyperandrogenemia increases adiposity and systemic inflammation, resulting in higher circulating leptin and IL-6 levels, which activate JAK/STAT3 signaling to induce renal inflammation, fibrosis, and hypertrophy. Moreover, increased JAK/STAT3 activation can increase renal AR expression and/or transcriptional activity, which additionally contributes to hyperandrogenemia-mediated renal injury and elevated BP." This hypothesis will be tested using a well-characterized and clinically relevant model of PCOS to test if hyperandrogenemia increases circulating IL-6 and leptin levels, which induce renal injury and BP increase via activating intrarenal JAK/STAT3 signaling (Aim 1), and to test if JAK/STAT3 signaling activation can directly increase renal AR expression and/or transcriptional activity thereby contributing to renal injury and BP increase in PCOS (Aim 2). The proposed project will use selective AR, IL-6, leptin, and JAK/STAT3 signaling blockers to demonstrate the role of the JAK/STAT3 in renal dysfunction and BP increase in PCOS, with the long-term goal of developing novel therapeutic targets to mitigate the onset and progression of the cardiorenal metabolic derangements in this syndrome.