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

This study examined the effect of transfer of overlapping regions of chromosome 5 that includes ([4A.sup.+]) or excludes ([4A.sup.-]) 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.sup.+] than in Dahl S or [4A.sup.-] rats. Mean arterial pressure (MAP) rose to 190 [+ or -] 7 and 185 [+ or -] 3 mmHg in Dahl S and [4A.sup.-] rats fed a high-salt (HS) diet for 21 days but only to 150 [+ or -] 5 mmHg in the [4A.sup.+] strain. Protein excretion increased to 423 [+ or -] 40 and 481 [+ or -] 37 mg/day in Dahl S and [4A.sup.-] rats vs. 125 [+ or -] 15 mg/day in the [4A.sup.+] strain. Baseline glomerular capillary pressure (Pgc) was lower in [4A.sup.+] rats (38 [+ or -] 1 mmHg) than in Dahl S rats (42 [+ or -] 1 mmHg). Pgc increased to 50 [+ or -] 1 mmHg in Dahl S rats fed a HS diet, whereas it remained unaltered in [4A.sup.+] rats (39 [+ or -] 1 mmHg). Baseline glomerular permeability to albumin ([P.sub.alb]) was lower in [4A.sup.+] rats (0.19 [+ or -] 0.05) than in Dahl S or [4A.sup.-] rats (0.39 [+ or -] 0.02). [P.sub.alb] rose to ~0.61 [+ or -] 0.03 in [4A.sup.-] and Dahl S rats fed a HS diet for 7 days, but it remained unaltered in the [4A.sup.+] rats. The expression of transforming growth factor-[beta]2 was higher in glomeruli of Dahl S rats than in [4A.sup.+] rats fed either a low-salt (LS) or HS diet. Chronic administration of a 20-HETE synthesis inhibitor (HET0016; 10 mg x [kg.sup.-1] x [day.sup.-1] sc) reversed the fall in MAP and renoprotection seen in [4A.sup.+] 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-[beta]; Dahl salt-sensitive rats; Rattus norvegicus 5; epoxyeicosatrienoic acids; dihydroxyeicosatrienoic acids; glomerulus; renal hemodynamics; kidney