Epigenetic Regulation of Kidney Fibrosis following AKI

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SUMMARY Episodes of acute kidney injury (AKI) are associated with an increased risk for chronic kidney disease (CKD); a permanent loss of kidney function. Following AKI, crosstalk between epithelial and interstitial cells is critical for kidney healing (adaptive response) but if prolonged fosters CKD (maladaptive). Evidence suggests that epigenetic modifiers, such as histone deacetylases (HDACs) and microRNAs (miRs), can become deranged leading to pathological conditions. For example, activation of kidney HDACs following AKI is hypothesized to exacerbate injury; however, we and others have demonstrated that HDACs are also necessary for epithelial repair. A gap in our knowledge exists in the kidney cell type specific, HDAC isoform-dependent mechanisms of repair or chronic injury in response to AKI. We identified that following AKI, HDAC1 is significantly increased in the kidney cortex including in fibroblasts and pericytes. Utilizing inducible, fibroblast- specific HDAC1 knockout (KO) mice, we found that fibroblast/pericyte HDAC1 results in myofibroblast activation and fibrosis. One potential target of HDAC1 may be miR-215-5p (miR215). miR215 is reduced by in vivo HDAC inhibition, and is increased by HDAC1 in kidney fibroblast/pericyte cells. We provide data that fibroblast miR215 is profibrotic. From these data, we propose to test the following hypotheses: Aim 1: To test the hypothesis that AKI-mediated fibrosis is dependent on activation of fibroblast/pericyte cell HDAC1. Aim 2: To test the hypothesis that AKI promotes miR215 dependent interstitial fibrosis in the kidney. The experiments proposed in this R01 will provide deep molecular evidence of epigenetic regulation of the kidney fibroblast/pericytes following AKI and we will determine the dynamic epigenetic patterning during CKD transition. Using both biased and unbiased approaches will result in the identification of novel pathways that likely be of therapeutic value to help attenuate AKI-CKD transition.