Project: Research project

Project Details


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.
Effective start/end date9/30/913/31/20


  • Medicine(all)