Tubular epithelial cell microRNA-17~92 regulates JAK/STAT signaling to protect females from acute kidney injury

Background: Ischemic acute kidney injury (AKI) is an abrupt decrease of kidney function from severe or prolonged reduction in renal perfusion. Renal tubular epithelial cell (TEC) dysfunction leads to irreversible tissue damage and in some cases mortality. It is known that the female sex is less susceptible to AKI, with increased likelihood of recovering kidney function and decreased likelihood of transitioning to end stage kidney disease. The mechanisms that drive sex differences in AKI remain unknown. This study investigated sex differences in microRNA (miR) regulation of the Janus kinase and Signal transducer and activator of transcription 3 (Jak/Stat3) cytokine cascade in TECs during AKI— in vivo using a miR-knockout & overexpression (KO/OE) murine model of AKI and in vitro using human donor renal tissue exposed to hypoxia. Hypothesis: We hypothesize that miR-17~92 is expressed and regulated in a sexually dimorphic manner in kidney TECs to control the Jak/Stat signaling pathway and protect females during AKI. By repressing pro-inflammatory and fibrotic EMT in female tubular epithelium during AKI, miR-17~92 would provide a novel point of early intervention in disease progression. Methods: Renal-specific OE/KO miR-17~92 C57BL/6J mice underwent unilateral ischemia-reperfusion injury (IRI) with a contralateral nephrectomy and kidney collection one day post-reperfusion. RT-qPCR quantified miR and mRNA expression in enriched proximal and distal TECs. Enriched donor renal epithelium and human kidney 2 cells (HK2–a model male renal line) underwent hypoxia to evaluate STAT3 signaling and miR regulation. MiR-17~92 expression was altered in HK2 cells to demonstrate regulation of Stat3 signaling. Results: We recapitulated the phenotype that female mice exhibit an improved ability to withstand renal injury compared to males with proportional duration of IRI. Males exhibited greater transcriptional induction of kidney injury marker (Kim-1) and Jak/Stat3 with comparable injury compared to female mice. MiR-17~92 expression was greater in female TECs before and after injury. Using luciferase reporters we validated that mir-17~92 targets and suppresses Jak/Stat3 signaling. OE miR-17~92 reduced the severity of AKI observed in male mice. Conversely, KO miR-17~92 mice of both sexes exhibit greater injury following IRI. The sex-differential phenotype was recapitulated in TECs from age-matched male and female human donor kidneys. TECs in females show greater baseline miR-17~92 expression compared to males. Hypoxia sex-differentially induced JAK/STAT3 mRNA and protein expression. By overexpressing miR-17~92, STAT3 activation was blunted in HK2 cells demonstrating the role of these miRs to regulate Stat3 signaling. Conclusion: These data provide the first example of sex-differential miR regulation in AKI. The elevated baseline expression of female miR-17~92 provide a novel mechanism in female kidney TEC protection from AKI to account for sex-differences in AKI. This work is supported by the NIH (DK102843 to MBB), (NIH R01DK102843-08S1 to AS), NIH (DK137419 and DK125015 to JH) and NIH (5R01DK131991 and 5R01DK064005 to RT) This abstract was presented at the American Physiology Summit 2025 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.