Since the initial observation that the renin-angiotensin system has profound effects on the kidney, angiotensin II has been implicated as having a pathophysiological role in renal disease. Despite this interest, our understanding of the pathogenic role of AII is based almost exclusively on the salutary effect of angiotensin I converting enzyme inhibitor (ACEI). ACEIs are now recognized to have a number of biological actions, independent of their effects mediated by specific inhibition of AII, including effects on other hormonal systems as well as direct cellular actions. Likewise, the role of AII on maturation is based on somewhat remote findings, i.e., proliferative effect of AII on cultured mesangial cells harvested from young animals and gene expression of renin and other enzymes involved in angiotensin II synthesis in embryos. This Project will therefore focus on the role of endogenous angiotensin II in development and disease. We will study the effects of AII on both pre- and postnatal development, as well as in the structural damage of the glomerulus secondary to postnatal renal injury [nephrotic syndrome and focal segmental glomerulosclerosis, (FGS)]. Our previous studies have demonstrated that ACEI retards postnatal maturational development of the glomerulus. We have also shown that ACEI can reverse progressive glomerular sclerosis in chronic renal failure. Most recently, we have cloned and sequenced the gene encoding angiotensin II receptor, thus enabling a new experimental approach to examine the effects of AII. Therefore, by using the AII receptor gene targeting technology provided by Core 2, and a unique oral AII receptor antagonist available to the Investigators, this Project will attempt to define the specific role of endogenous AII in maturation and disease processes. The role of AII in prenatal development will be examined by inactivating the AII receptor gene, either by gene targeting or with specific AII receptor, and assessing the effects on development. The role of angiotensin II in postnatal glomerular disease will be examined in the puromycin nephropathy model. We will assess whether early therapy with ACEI or specific AII receptor antagonist affects the subsequent course to FGS, and if such effects of ACEI are solely attributable to effects on AII. We will also examine if such therapy, when initiated after establishment of FGS, can alter subsequent course of focal glomerular sclerosis (FGS).
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