Transfer of the CYP4A region of chromosome 5 from Lewis to Dahl S rats attenuates renal injury

摘要

Transfer of the CYP4A region of chromosome 5 from Lewis to Dahl S rats attenuates renal injury. Am J Physiol Renal Physiol 295: F1764-F1777, 2008. First published October 8, 2008; doi: 10.1152/ajprenal.90525.2008.-This study examined the effect of transfer of overlapping regions of chromosome 5 that includes (4A+) or excludes (4A~) the cytochrome P-450 4A (CYP4A) genes from the Lewis rat on the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and the development of hypertension-induced renal disease in congenic strains of Dahl salt-sensitive (Dahl S) rats. The production of 20-HETE was higher in the outer medulla of 4A+ than in Dahl S or 4A~ rats. Mean arterial pressure (MAP) rose to 190 +- 7 and 185 +- 3 mmHg in Dahl S and 4A" rats fed a high-salt (HS) diet for 21 days but only to 150 +- 5 mmHg in the 4A+ strain. Protein excretion increased to 423 +- 40 and 481 +-37 mg/day in Dahl S and 4A~ rats vs. 125 +- 15 mg/day in the 4A+ strain. Baseline glomerular capillary pressure (Pgc) was lowerin 4A+ rats beta8 +- 1 mmHg) than in Dahl S rats (42 +- 1 mmHg). Pgc increased to 50 +- 1 mmHg in Dahl S rats fed a HS diet, whereas it remained unaltered in 4A+ rats beta9 +- 1 mmHg). Baseline glomerular permeability to albumin (fait.) was lower in 4A+ rats (0.19 +- 0.05) than in Dahl S or 4A~ rats (0.39 +- 0.02). Paib rose to -0.61 +- 0.03 in 4A~ and Dahl S rats fed a HS diet for 7 days, but it remained unaltered in the 4A+ rats. The expression of transforming growth factor-|32 was higher in glomeruli of Dahl S rats than in 4A+ rats fed either a low-salt (LS) or HS diet. Chronic administration of a 20-HETE synthesis inhibitor (HET0016; 10 mg-kg"1 -day"1 sc) reversed the fall in MAP and renoprotection seen in 4A+ rats. These results indicate that the introgression of the CYP4A genes from Lewis rats into the Dahl S rats increases the renal formation of 20-HETE and attenuates the development of hypertension and renal disease