Hypertension affects 25% of the world population and is a major cause of cardiac, cerebral and renal mortality, yet in 90% of cases the pathogenesis remains unknown. Recently, we proposed a pathway for the development of salt dependent hypertension in man. A major concept in the pathway is that acquired injury to the kidney results in the inability of the kidney to excrete salt, and that this is the consequence of structural (tubular, interstitial, vascular) and functional (generation of vasoactive mediators) changes. In this proposal we will specifically address aspects of this hypothesis.
In aim 1, we will determine if tubulointerstitial injury induced by phenylephrine or hypokalemia results in salt-dependent hypertension, identify the structural and functional changes in the renal tissue, and demonstrate that the hypertension can be transferred to naive animals by renal transplantation.
In aim 2 we will explore the role of osteopontin in mediating both the structural and functional changes (nitric oxide generation) in murine models of tubulointerstitial disease using knock-out and wild type mice, and will explore the regulation of nitric oxide synthesis in cultured endothelial cells by osteopontin.
In aim 3 we will address the role of various vasoactive mediators in these hypertensive models by administering agents that either stimulate or block their action. These studies should provide new insights into the pathogenesis and treatment of salt-dependent hypertension.

Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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