Obstructive nephropathy is the renal disease caused by urinary tract obstruction. The latter is a common entity in all age groups. It was the fourth leading diagnosis at hospital discharge among male patients with kidney and urologic disorders and the sixth among females with such disorders. In acute obstruction studied in experimental animals renal blood flow and GFR are decreased, due in part of increased synthesis and/or activity of vasoconstrictors. The first, and major component of this project focuses on nitric oxide (NO) in obstructive nephropathy. NO, a product of arginine metabolism through NO synthase, is a powerful vasodilator that affects renal hemodynamics and systemic blood pressure. We will examine the hypothesis that in obstructive nephropathy infiltration of the kidney by macrophages alters renal hemodynamics not only through changes in vasoconstrictor levels but also through changes in the levels of arginine ad its metabolites, particularly No. We will study: 1) the effect of infiltrating macrophages on the metabolism of arginine and the generation of NO; 2) the mechanisms by which arginine administration prevents macrophage infiltration of the kidney; 3) the interrelationships between vasoconstrictors (angiotensin II, thromboxane A2) and NO generation; 4) the renal distribution and activity of inducible and constitutive NO synthase in obstructive nephropathy. Renal tubular function is also affected in obstructive nephropathy, leading to decreased reabsorption of solutes and water, and impaired secretion of H+ and K+. These abnormalities may reflect impaired responses of the obstructed kidney to effectors hormones. There are changes in quanine nucleotide binding proteins (G-proteins) in the kidney after the onset of obstruction. Since G-protein have a key role in transmembrane signaling, we will test the hypothesis that in obstruction changes in G- proteins contribute to impaired hormonal reponsiveness and decreased ion and solute transport. The proposed studies will utilize physiological, biochemical and molecular biology techniques to explore these hypotheses. We will examine the interactions between vasoconstrictors and NO by inhibiting vasoconstrictor production. In addition, using appropriate probes we will measure the activity of NO synthase derive either from invading macrophages or renal cells in obstructed kidneys. We will characterize the G-proteins in different segment of the nephron and relate changes in hormonal reponsiveness and in specific transporters (Na+/H+, H+-ATPase) to the changes in G-proteins determined by immunochemistry, PCR techniques, Northern blots, etc. These studies should elucidate some of the mechanisms affecting renal function and structure in urinary tract obstruction and ultimately suggest new therapeutic modalities for obstructive nephropathy.

Project Start
1997-01-01
Project End
1997-12-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
32
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110
Slatopolsky, Eduardo (2011) The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder. Kidney Int Suppl :S3-8
Morrissey, Jeremiah; Guo, Guangjie; Moridaira, Kazuaki et al. (2002) Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease. J Am Soc Nephrol 13:1499-508
Morrissey, Jeremiah; Hruska, Keith; Guo, Guangjie et al. (2002) Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol 13 Suppl 1:S14-21
Hruska, Keith A (2002) Treatment of chronic tubulointerstitial disease: a new concept. Kidney Int 61:1911-22
Hruska, K A; Guo, G; Wozniak, M et al. (2000) Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am J Physiol Renal Physiol 279:F130-43
Klahr, S (1999) Mechanisms of progression of chronic renal damage. J Nephrol 12 Suppl 2:S53-62
Hemken, P; Guo, X L; Wang, Z Q et al. (1992) Immunologic evidence that vacuolar H+ ATPases with heterogeneous forms of Mr = 31,000 subunit have different membrane distributions in mammalian kidney. J Biol Chem 267:9948-57
Reyes, A A; Robertson, G; Jenden, D J et al. (1992) Subdiaphragmatic vagotomy in rats induces systemic hypertension and sodium retention. Miner Electrolyte Metab 18:375-81
Portilla, D; Mordhorst, M; Bertrand, W et al. (1988) Protein kinase C modulates phospholipase C and increases arachidonic acid release in bradykinin stimulated MDCK cells. Biochem Biophys Res Commun 153:454-62