Renal Myofibroblast: Origins, Activation and Fate

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DESCRIPTION (provided by applicant): End-stage renal disease (ESRD) is one of the most devastating diseases with great morbidity and mortality, and the number of patients is on the rise worldwide. Despite diverse primary etiologies, the pathogenesis of chronic renal diseases progressing to ESRD is a remarkably monotonous process characterized by relentless accumulation of extracellular matrix (ECM) leading to widespread tissue fibrosis. Because renal fibrosis is preceded by activation of (z-smooth muscle actin-positive, matrix-producing myofibroblasts, a possible key to an effective therapy for progressive renal fibrosis is to find a strategy that inhibits the activation of renal myofibroblasts in the diseased kidney. Despite this, little is known as to the origins, activation process, and fate of myofibroblasts. In this application, we hypothesize that myofibroblasts originate from diverse origins with distinct dynamics in the pathogenesis of renal interstitial fibrosis and that the ultimate fate of myofibroblasts includes reversal to quiescent fibroblasts, apoptosis, and re-differentiation to tubular epithelial cells. We propose to test these hypotheses by investigating the cellular origins, the genes and signaling critical for their activation and the destiny of activated myofibroblasts in the kidney both in vivo and in vitro. We will also evaluate the therapeutic efficacy of new treatment regimes aimed at inhibition of myofibroblast activation for chronic renal fibrosis. These will be accomplished in the four specific aims, which address the origins, activation, fate and therapeutic intervention of myofibroblast cells at whole animal, cellular iand molecular levels. Resolution of these fundamental issues will not only provide mechanistic insights into the pathogenesis of chronic renal fibrosis, but also offers unique opportunities for designing rational strategies for the treatment of this devastating disease.