This study examined the effect of transfer of overlapping regions of chromosome 5 that includes (4A⁺) or excludes (4A^-) the CYP4A genes from the Lewis rat on the renal production of 20-HETE and the development of hypertension-induced renal disease in congenic strains of Dahl S rats. The production of 20-HETE was higher in the outer medulla of 4A⁺ than in Dahl S or 4A^- rats. 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 versus 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, while it remained unaltered in 4A⁺ rats (39±1 mmHg). Baseline glomerular permeability to albumin (Palb) was lower in 4A⁺ rats (0.19±0.05) than in Dahl S or 4A^- rats (0.39±0.02). Palb rose to approximately 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 TGF-2 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/day, s.c.) 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.