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

¹Kidney Disease Center, ²Human and Molecular Genetics Center, Departments of ³Physiology, ⁴Medicine, ⁵Pediatrics, and ⁶Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin; and ⁷Departamento de Fisiologia, Facultad de Medicina, Universidad de Murcia, Murcia, Spain

Submitted 1 September 2008 ; accepted in final form 3 October 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 lower in 4A⁺ rats (38 ± 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 (39 ± 1 mmHg). Baseline glomerular permeability to albumin (P_alb) was lower in 4A⁺ rats (0.19 ± 0.05) than in Dahl S or 4A^– rats (0.39 ± 0.02). P_alb 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-β2 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.

hypertension; glomerulosclerosis; 20-hydroxyeicosatetraenoic acid; transforming growth factor-β; Dahl salt-sensitive rats; Rattus norvegicus 5; epoxyeicosatrienoic acids; dihydroxyeicosatrienoic acids; glomerulus; renal hemodynamics; kidney

This article has been cited by other articles:

				K. Inoue, K. Sodhi, N. Puri, K. H. Gotlinger, J. Cao, R. Rezzani, J. R. Falck, N. G. Abraham, and M. Laniado-Schwartzman Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE Am J Physiol Renal Physiol, October 1, 2009; 297(4): F875 - F884. [Abstract] [Full Text] [PDF]