The objective of this grant is to determine whether the intrarenal renin angiotensin system modulates the hyperplastic growth of the tubular epithelium and the process of cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). The general hypothesis is that the renin angiotensin system is an important component of the complex network of peptide growth factors and hormones that control tubular epithelial cell proliferation and its blood supply in ADPKD. In preliminary studies, we have demonstrated the association of hypertension and ADPKD, the adverse effect of hypertension on kidney survival in this disease, the central role of the renin angiotensin system in the pathogenesis of this hypertension, the correlation between the severity of cystic disease and the activation of the renin angiotensin system in a chemically induced experimental model, the presence of renin in the tubular epithelial cells and cyst fluids, and the synthesis of renin by cyst derived, cultured epithelial cells. For the proposed studies, we will use a new rat mutant with ADPKD, as well as tubular epithelial cell cultures derived from these rats and from human polycystic kidneys. We will determine (1) whether the blockade of the renin angiotensin system inhibits cystogenesis in ADPKD, (2) whether genetically determined increased expression of the renin gene enhances cystogenesis in this disease, (3) whether cultured epithelial cells derived from ADPKD kidneys, as compared to normal kidneys, have an increased capacity to synthesize renin, angiotensinogen, angiotensin converting enzyme, and peptide growth factors or are more sensitive to the growth promoting effects of angiotensin II and peptide growth factors, and (4) whether the presence and localization of renin, angiotensinogen, angiotensin converting enzyme, peptide growth factors, and receptors for angiotensin II and peptide growth factors are abnormal in ADPKD. The results of these studies will augment the understanding of the pathogenesis of cyst formation and hypertension in ADPKD and are likely to have a significant impact on the treatment of this disease.
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