National Institute of Diabetes and Digestive and Kidney Diseases 1R01DK144010-01A1

The Role of Epithelial MicroRNAs to Confer Sex-Specific Renoprotection in Acute Kidney Injury

This award funds research investigating how epithelial microRNAs, particularly the miR-17~92 cluster, contribute to sex-specific protection against acute kidney injury by modulating inflammatory and fibrotic pathways in kidney tubular epithelial cells.

Description

Acute kidney injury (AKI) is a sudden loss of kidney excretory function that can result from many insults including reduced blood flow to the kidney (ischemia). Sex differences in the degree of injury have been noted, the causes of which are still not known. While a role for microRNAs (miRs) in AKI has been recognized, there are few reports of sex differences in miR regulation after injury. We hypothesize that sex-differentially expressed miRs including the miR-17~92 cluster represses proinflammatory and pro-fibrotic signaling pathways in female tubular epithelium during AKI. We propose to investigate sex differences in miRNA regulation in tubular epithelial cells using two models of AKI. We will use primary human kidney cultured cells to confirm miR-17~92 induction with injury (using cisplatin or hypoxia) or stimulation using interleukin-6 (Il6). We will assess protein and mRNA expression for inflammation, EMT, oxidative stress, and adaptive repair to demonstrate the immunomodulatory role of miR-17~92 in both mouse and primary human TECs. Using established tubule-specific inducible miR-17~92 knockout murine models, we will induce AKI and compare differences in male and female inflammatory response and functional outcomes when expression of the miR cluster is altered. We will evaluate indices of AKI, including renal function (BUN and serum creatinine), physical injury (histological kidney injury scoring), and mRNA and protein expression. We will knockout and overexpress miR-17~92 in vitro to demonstrate the role of miR-17~92 on Jak/Stat signaling in tubular epithelial cells (TECs). This will define a novel role for miR-17~92 in the TECs to protect against ischemic-AKI development in vivo and in vitro, demonstrating that these miRs drive sex differences observed in injury cascade.

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