Regulation of tubulointerstitial crosstalk by microRNAs in renal fibrosis

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(PLEASE KEEP IN WORD, DO NOT PDF) An estimated 37 million people (15% of the population) in the United States have chronic kidney disease. There are currently no specific interventions to decrease the progression of chronic kidney disease, which ultimately leads to renal failure necessitating kidney transplant or dialysis. Regardless of underlying etiology, advancing CKD ultimately results in irreversible nephron loss and renal fibrosis. Fibrosis is part of the normal repair process triggered in response to injury, and dysregulation of this process results in the pathological accumulation of extracellular matrix proteins, primarily collagens. Current therapies have limited effectiveness and at most delay the progression of chronic kidney disease. Understanding the molecular mechanisms that drive the early accumulation of ECM proteins in renal fibrosis will inform novel therapeutic approaches to CKD. Our laboratory was the first to demonstrate that conditional loss of the miR-17~92 cluster (comprised of miR-17, miR-18, miR-19a, miR-19b, miR-20a and miR-92a) in nephron progenitors and their derivatives results in renal hypodysplasia and chronic kidney disease in mice. We now have preliminary data that inducible loss of miR-17~92 in adult renal epithelia results in increased susceptibility to renal fibrosis, and conversely that inducible gain of miR-17~92 in adult renal epithelia is protective against renal fibrosis. Our central hypothesis is that miR-17~92 in renal epithelia functions to limit renal fibrosis. To test this hypothesis, we propose to determine whether the miR-17~92 cluster is sufficient to protect against renal fibrosis in mice.