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Mechanism of hypertensive nephropathy in the Dahl/Rapp rat: a primary disorder of vascular smooth muscle

Nephrology Research and Training Center, Comprehensive Cancer Center, and Cell Adhesion and Matrix Research Center, Division of Nephrology, Departments of Medicine and of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham; and Department of Veterans Affairs Medical Center, Birmingham, Alabama

Submitted 8 June 2004 ; accepted in final form 27 September 2004

The Dahl/Rapp salt-sensitive (S) rat is a model of salt-sensitive hypertension and hypertensive renal disease. This study explored the role of vascular remodeling in the development of renal failure in S rats. Groups of S and Sprague-Dawley rats were given 0.3 and 8.0% NaCl diets for up to 21 days and evidence of smooth muscle proliferation identified using immunohistochemistry that showed nuclear accumulation of proliferating cell nuclear antigen and 5-bromo-2'-deoxy-uridine. Compared with the other three groups, S rats on 8.0% NaCl diet showed increased nuclear labeling of cells of the aorta and arteries and arterioles of the kidney by the end of the first week of study. Progressive luminal narrowing of the interlobular arteries and preglomerular arterioles occurred in S rats over the 3 wk on the 8.0% NaCl diet. Accumulation of pimonidazole adducts and nuclear accumulation of hypoxia-inducible factor-1 (HIF-1) were used as markers of tissue hypoxia. By the end of the second week of study, pimonidazole levels increased in S rats on 8.0% NaCl diet and deposition was apparent in tubular cells in the cortex and medulla. At the completion of the experiment, HIF-1 levels were increased in nuclear extracts from the cortex and medulla of S rats on this diet, compared with the other three groups of rats. The data demonstrated a disorder of the vascular remodeling process with proliferation of vascular smooth muscle cells temporally followed by development of tissue hypoxia in the hypertensive nephropathy of S rats on 8.0% NaCl diet.

salt-sensitive hypertension; kidney disease; hypoxia; hypoxia-inducible factor-1; pimonidazole

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