The application seeks continued funding for an interactive team of clinical and basic scientists dedicated to the investigation of childhood nephrotic syndrome and closely related diseases, with the objective of identifying the pathogenic role of specific gene products and defining their sequelae in renal injury. Recognizing the significance of the renin-angiotensin system (RAS) in these settings as reflected by the therapeutic effectiveness of inhibitors of the components of RAS in animals and/or humans, we also perceive the clear advantage of taking genetic approaches in defining RAS's specific contributory components and their mode of participation in renal tissue injury. Project 0001 will define the biological events in glomerulosclerosis that are dependent upon vs. independent of angiotensin II (Ang II). For this purpose, DNA recombinant mice with 'regional' Ang receptor gene knock-out developed in our Center will be used. Project 0004 will examine the significance of gene variants within RASE for the progressive loss of renal function in obstructive/reflux nephrophath. The PROJECT will expand into determination of the functional significance of ACE gene activity in local tissue injury by examining human genome and a DNA recombinant mouse model. There is growing body of evidence to indicate that Ang II exerts significant functions through ANG II type 2 receptor (AT2) in the kidney. Renin, in contrast to more downstream steps of RAs, has not been well studied in terms of its regulatory role due to the lack of experimental tools. Based on the encouraging results of our renin knock-out study, Project 0005 proposes a series of experiments for defining the role of disregulation of renin in the renal tissue remodeling process.
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