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Supressor ANGII Determines Acute &Chronic Renal Injury

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Angiotensin II (Angll) is a key regulator of blood pressure and renal function. Abnormalities in the regulation of Angll lead to hypertension (HTN) and chronic renal insufficiency (CRI), and therapies that block Angll are among the most effective in treating HTN and in delaying progression of CRI;indeed, the injurious effects of Angll now receive more attention than its physiological role. However, a limitation in our understanding of the mechanisms by which Angll exacerbate HTN and CRI arises from the fact that much of our knowledge is derived from studies that utilize pressor doses of Angll, in which Angll levels are many-fold higher than that seen in clinical scenarios. In the current proposal, we employ the chronic administration of sub-pressor doses of Angll (SP-Angll) which, while increasing intrarenal Angll levels, maintains circulating Angll within physiologic limits. SP-Angll is characterized by oxidant-dependent increases in renal vascular reactivity, blunting of salt-induced cortical hyperemia, and attendant salt-sensitive HTN;additionally, SP-Angll upregulates inflammatory chemokines (i.e. monocyte chemoattractant protein-1;MCP-1) which promote renal injury. However, SP-Angll also induces adaptive pathways (heme oxygenase-1;HO-1) which mitigate the deleterious effects of Angll, and in this regard, we recently found that SP-Angll-induced HO-1 conferred an unexpected acquired resistance to acute renal ischemic injury. Our overall goal is to uncover the mechanisms by which interactions between SP-Angll-induced MCP-1 /HO-1 determine the divergent effects of SP-Angll on acute and chronic renal injury, and salt-sensitive HTN. We propose 3 aims. In AIM #1 we will test the hypothesis that SP-Angll upregulates MCP-1, which in turn modulates renal vascular function and causes salt-sensitivity. In AIM #2 we will assess the interactions between MCP-1 and HO-1 in determining progression of chronic renal injury induced by SP-Angll, and their modulation by salt intake. In AIM #3 we will examine the cellular and hemodynamic mechanisms by which SP-Angll induces acquired resistance to acute renal failure, with emphasis on HO-1-dependent pathways. In summary, this application addresses how a specific hormone, Angll, can influence the course of three distinct, but related common illnesses: HTN, CRI and acute renal failure. Specifically, we investigate the mechanisms by which Angll initiates inflammatory cascades (that promote HTN and CRI), while simultaneously generating factors that protect against acute injury. Understanding such mechanisms, may help uncover novel therapeutic strategies in the treatment of these disorders, the importance of which is underscored by the enormous medical and financial burden that these ailments impose on the healthcare system.

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