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. This competitive renewal application is a continuation of our long-term efforts to develop rational strategies for therapeutic intervention of chronic kidney diseases (CKD) that progress to ESRD. Despite diverse primary etiologies, the pathogenesis of CKD is characterized by chronic inflammatory infiltration and relentless accumulation of extracellular matrix (ECM) leading to widespread tissue fibrosis. Thus, developing a scheme to inhibit inflammation and fibrosis may be a key strategy for the treatment of CKD. Studies in previous project period of this application suggest that hepatocyte growth factor (HGF) is potent anti-fibrotic, anti-inflammatory factor that prevents the onset and progression of CKD in animal models. In this continuation application, we propose to investigate the molecular mechanism by which HGF elicits its beneficial actions. The central hypotheses to be tested are that: 1) HGF inhibits renal fibrosis by antagonizing the fibrogenic action of TGF-?/Smad signaling;2) HGF suppresses renal inflammation by blocking pro-inflammatory NF-kB signaling;and 3) HGF interacts synergistically with TGF-?1 to suppress renal inflammation. These hypotheses will be addressed by three specific aims at the whole animal, the cellular, the signal transduction and molecular levels, respectively.
Aim 1 is designed to investigate the molecular mechanism underlying HGF induction of SnoN expression in tubular epithelial cells and to evaluate the therapeutic efficacy of SnoN gene transfer for chronic kidney fibrosis in vivo.
Aim 2 is to understand the mechanism underlying HGF blockade of renal inflammation and NF-kB signaling and investigate the interplay between HGF and TGF-?1 leading to synergistic inhibition of renal inflammation.
Aim 3 is to evaluate the role of HGF/c-met signaling in mediating the anti-fibrotic action of peroxisome proliferator- activated receptor-y. These studies will provide fundamental and important insights into understanding the mechanism underlying the therapeutic efficacy of HGF for CKD. Ultimately, these studies may lead to development of novel strategies to alter the course of human kidney disease by manipulating the activity of HGF signaling system.
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