Progression of chronic renal disease still represents one of the biggest challenges for scientists, as it leads a large number of patients towards end stage renal failure (ESRF) and thus requiring dialysis therapy. Scarring of the kidney, which is caused by a progressive fibrosis leading to impairment of kidney function, occurs due to a variety of primary insults, such as diabetes mellitus, hypertension, primary glomerulopathies, autoimmune diseases, toxic injury or congenital abnormalities. The main cellular events that mediate progression of tubulointerstitial fibrosis are activation (enhanced proliferation and extracellular matrix deposition) of resident fibroblasts and epithelial-mesenchymal transition (EMT, tubular epithelial cells becoming fibroblasts). Thus, requirements to achieve reversal of chronic renal injury are the inhibition of fibroblast activation, prevention or even reversal of EMT, and also enhancement of matrix degradation, which should exceed interstitial matrix deposition. In this regard, TGF-beta has been identified as the major growth factor that can participate in the damage of kidney architecture and function. Experiments proposed in this grant application are based on the recent observation that bone morphogenic protein 7 (BMP-7), a growth factor, which is involved in regulation of kidney development, could reverse chronic renal disease in a mouse model of ESRF. BMP-7 was identified as an antagonist of TGF-beta induced EMT involving kidney tubular epithelial cells. However, the utility of BMP-7 as a drug against chronic kidney disease is still underappreciated. Thus, an in depth understanding of BMP-7 mediated action in the kidney is important to understand the potential of BMP-7 as a therapeutic agent. Experiments proposed here attempt to 1) To determine the functional BMP-7 receptor/s in the kidney, 2) to determine the physiological function of BMP-7 in the kidney and 3) to investigate the induction of mesenchymal-epithelial-transition (MET) by BMP-7 as a possible mechanism for repair of injured adult kidney. Successful completion of studies proposed in this grant application will identify the relative contribution and significance of BMP-7 receptors in the kidney. The physiological role of BMP-7 in kidney health and pathology will be established. These studies will directly benefit the development of this molecule in the clinic as a drug for patients with kidney fibrosis.
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