Abstract: SA-PO0282
MicroRNA-17~92 Regulates JAK/STAT Signaling in Tubular Epithelial Cells to Protect Female Mice from AKI
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Suda, Amanda, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Emlet, David R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Tan, Roderick J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Ho, Jacqueline, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Butterworth, Michael, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
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 Jak/Stat cytokine cascade in proximal tubules (PT) during AKI—in vivo using a miR-knockout (KO) model of AKI and in vitro using human donor renal PT cells.
We hypothesize that miR-17~92 is expressed and regulated in a sexually dimorphic manner in renal TECs to dampen 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 RNAseq quantified mRNA expression in enriched PT cells. Renal epithelium from male and female donors underwent injury 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, Lipocalin-2, and Jak/Stat, as well as functional readouts BUN and SCr with injury compared to female mice. MiR-17~92 expression was greater in female proximal tubules before and after injury. Using luciferase reporters we validated that mir-17~92 targets and suppresses Jak/Stat signaling. KO female mice exhibit greater injury following IRI – matching male severity of injury. The sex-differential phenotype was recapitulated in PTs from age-matched male and female human donor kidneys. PTs in females show greater baseline miR-17~92 expression compared to males. Injury sex-differentially induced JAK/STAT mRNA and protein expression. Introducing miR-17~92 mimics blunted STAT activation in human kidney PTs, 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.
Acknowledgment
This work is supported by the KidneyCure Pre-Doctoral Fellowship Award Program, NIH (DK102843 to MBB), (NIH R01DK102843-08S1 to AS), NIH (DK137419 and DK125015 to JH) and NIH (5R01DK131991 and 5R01DK064005 to RT)
Funding
- NIDDK Support