Our previous work indicates that regression of glomerulosclerosis can be achieved by high dose angiotensin inhibition. We have established that the type 1 receptor antagonist (AT1 RA) not only decreases extracellular matrix (ECM) synthesis, but is also linked to enhanced ECM degradation by decreasing expression of plasminogen activator inhibitor-1 (PAI-1), which promotes fibrin/matrix degradation and modulates cell migration and growth. Decreased PAI-1 induced by AT1RA is tightly linked to regression of sclerosis. Based on these findings, we now hypothesize that regression of existing sclerosis is mediated via coordination of 2 pivotal processes: resorption of existing areas of scar and new capillary growth. We further hypothesize that AT1 RA promotes regression by decreasing ECM accumulation, as well as by promoting glomerular capillary growth driven by key angiogenic factors, vascular endothelial-derived growth factor (VEGF)-A and the angiopoietins 1 and 2. VEGF-A and angiopoietin-1 (Ang1) are normally derived from the podocyte. We will examine mechanisms of capillary growth by genetic manipulations with systemic and/or podocyte-specific overexpression of VEGF-A and Ang1 and also Ang2, and inhibition of the renin aldosterone angiotensin system (RAAS). Inducible podocyte-specific transgenic mice will allow determination of the impact of these capillary growth mechanisms in regression. We have established primary podocyte cultures from wildtype and genetically manipulated mice, and obtained a glomerular endothelial cell (GEN) line, which will allow us to explore effects of podocyte injury and AT1RA on capillary growth and ECM regulation. We will use these novel in vivo models together with in vitro experiments to examine the interactions of the RAAS, PAI-1, ECM modulation and capillary growth to determine mechanisms of regression of glomerulosclerosis. 2) Relevance: Inexorable scarring of the kidney's vascular filtering units, the glomeruli, is a major cause of kidney failure, necessitating dialysis or transplant. Reversal of this process can be accomplished by inhibiting angiotensin, a key hormone that promotes hypertension and scarring. We will investigate how we can achieve breakdown of scar tissue and growth of new cells in concert to reverse scarring, and have more open, less scarred glomeruli that can filter better. ? ? ?
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