Abstract

The overall goal of this proposal is to elucidate the contributions of angiotensin II (A II) and endothelin (ET) to the progression of renal insufficiency. Rat models of chronic renal insufficiency will be used, and micropuncture, and morphologic and biochemical techniques will constitute the major methodologies employed.
Four Specific Aims are enumerated to accomplish this objective.
Specific Aim 1 will examine how the renin-angiotensin system contributes to hypertension and glomerular injury in renal insufficiency. The proposed studies will test the hypothesis that intrarenal AII activity is increased while circulating AII levels remain normal following renal ablation.
Specific Aim 2 will identify the contribution of ET to altered glomerular function and structure in renal insufficiency.
Specific Aim 3 will assess the interaction of AII mediated hypertension and local ET production in renal insufficiency. Initial studies will test the hypothesis that blood pressure reduction with an AII blocker reduces ET expression and thereby normalizes the hemodynamic actions of ET in remnant glomeruli. The fourth Specific Aim will assess the contribution of AII to tubulointerstitial injury. Recent studies suggest that AII promotes interstitial fibrosis independent of its effects on blood pressure and glomerular function. It is anticipated that with a better understanding of when and how AII contributes to the progression of renal disease, it will be feasible to more rationally prescribe AII antagonist therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052841-02
Application #
2770639
Study Section
Special Emphasis Panel (ZRG4-GMB (04))
Project Start
1997-09-01
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Rudnicki, M; Eder, S; Perco, P et al. (2007) Gene expression profiles of human proximal tubular epithelial cells in proteinuric nephropathies. Kidney Int 71:325-35
Meyer, Timothy W; Walther, Jason L; Pagtalunan, Maria Enrica et al. (2005) The clearance of protein-bound solutes by hemofiltration and hemodiafiltration. Kidney Int 68:867-77
Martinez, Andres W; Recht, Natalie S; Hostetter, Thomas H et al. (2005) Removal of P-cresol sulfate by hemodialysis. J Am Soc Nephrol 16:3430-6
Meyer, Timothy W; Leeper, Evonne C; Bartlett, Derek W et al. (2004) Increasing dialysate flow and dialyzer mass transfer area coefficient to increase the clearance of protein-bound solutes. J Am Soc Nephrol 15:1927-35
Rudnicki, Michael; Eder, Susanne; Schratzberger, Gabriele et al. (2004) Reliability of t7-based mRNA linear amplification validated by gene expression analysis of human kidney cells using cDNA microarrays. Nephron Exp Nephrol 97:e86-95
Meyer, Timothy W (2003) Tubular injury in glomerular disease. Kidney Int 63:774-87
Rasch, Ruth; Nyengaard, Jens R; Marcussen, Niels et al. (2002) Renal structural abnormalities following recovery from acute puromycin nephrosis. Kidney Int 62:496-506
Mackie, Fiona E; Meyer, Timothy W; Campbell, Duncan J (2002) Effects of antihypertensive therapy on intrarenal angiotensin and bradykinin levels in experimental renal insufficiency. Kidney Int 61:555-63
Oberbauer, R; Schwarz, C; Regele, H M et al. (2001) Regulation of renal tubular cell apoptosis and proliferation after ischemic injury to a solitary kidney. J Lab Clin Med 138:343-51
Javaid, B; Olson, J L; Meyer, T W (2001) Glomerular injury and tubular loss in adriamycin nephrosis. J Am Soc Nephrol 12:1391-400

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