MicroRNA-17~92 Regulates JAK/STAT Signaling in Tubular Epithelial Cells to Protect Female Kidneys from AKI

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. The female sex is less susceptible to AKI, but mechanisms that drive sex differences in AKI remain unknown. This study investigated sex differences in microRNA (miR) regulation of the Janus kinase/Signal transducer and activator of transcription (Jak/Stat) cytokine cascade in TECs during AKI—in vivo using a miR-knockout (KO) model of AKI and in vitro using human donor renal TECs exposed to hypoxia. We hypothesize that miR-17~92 is expressed and regulated in a sexually dimorphic manner in renal TECs to control the Jak/Stat signaling pathway and protect females during AKI. Methods: Renal-specific KOmiR-17~92 C57BL/6J mice underwent unilateral ischemia-reperfusion injury with a contralateral nephrectomy and kidney collection one day post-reperfusion. RT-qPCR quantified miR and mRNA expression in enriched TECs. Renal epithelium from male and female donors underwent hypoxia to evaluate STAT signaling and miR regulation. 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 molecule-1 and Jak/Stat with injury compared to females. 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/Stat signaling. KO 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/STAT mRNA and protein expression. By overexpressing miR-17~92, STAT activation was blunted in human kidney TECs, demonstrating the role of these miRs to regulate STAT 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. Funding: NIDDK Support - NIDDK Support, NIDDK Support