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1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Kidney Disease Center, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA
3 Physiology, Medical University of Ohio, Toledo, Ohio, USA
4 Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: rroman{at}mcw.edu.
The present study examined whether transfer of overlapping regions of chromosome 5 that include (4A+) or exclude the cytochrome P450 (CYP) 4A genes from the Lewis rat alters the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and/or the development of hypertension in congenic strains of Dahl salt-sensitive (S) rats. The expression of CYP4A protein and the production of 20-HETE in the renal outer medulla was greater in the 4A+ congenic strain than the levels seen in S rats or in overlapping control congenic strains that exclude the CYP4A region. Mean arterial pressure (MAP) rose from 122±2 to 190±7 mmHg in S rats and from 119±2 and 123±2 to 189±7 and 187±3 mmHg in the two control congenic strains fed an 8.0% NaCl diet for 3 weeks. In contrast, MAP only increased from 112±2 to 150±5 mmHg in the 4A+ congenic strain. Chronic blockade of the formation of 20-HETE with N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide (TS-011; 1 mg/Kg, b.i.d.) restored the salt-sensitive phenotype in the 4A+ congenic strain and MAP rose to 181±6 mmHg after an 8.0% NaCl dietary challenge. TS-011 had no effect on the development of hypertension in S rats or the two control congenic strains. The pressure-natriuretic and diuretic responses were 5-fold greater in the 4A+ congenic strain than in S rats. These results indicate that transfer of the region of chromosome 5 between markers D5Rat108 to D5Rat31 from the Lewis rat into the Dahl S genetic background increases the renal production of 20-HETE, improves pressure-natriuresis and opposes the development of salt-induced hypertension.
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