Evaluation of P4504a Genes for Hypertension and Renal Disease Using Chromosome 5 Congenic Strains of Dahl S Rats.
P4504A1 and 4A2 genes are differentially expressed in the kidney and cosegregate with blood pressure in an F2 cross of Dahl S and Lewis rats; however, it is unclear whether this pathway plays a causal or secondary role in the development of hypertension. The present study examined whether transfer of overlapping segments of chromosome 5 from D5Rat84 to D5Rat34 that excludes (4A- strain) or includes all four P4504A genes(4A+ strain),or just the 4A3 and 4A8 genes (4A3,8+ strain), of a Lewis rat alters blood pressure, proteinuria, and renal injury in 12 week old congenic strains of Dahl S rats fed a high salt diet (8% NaCl) for 3 weeks. MAP measured in conscious rats using a chronic catheter averaged 188 ± 3 mm Hg in male Dahl S rats (n=24), 190 ± 3 mm Hg in the 4A- congenic strain (n=24), 169 ± 4 mm Hg in the 4A+ congenic strain (n=30), and 172 ± 3 mm Hg in the 4A3,8+ strain (n=33). Transfer of the P4504A region also significantly reduced proteinuria, renal hypertrophy, and the degree of glomerular and tubulointerstitial injury. Protein excretion averaged 246 ± 22 mg/day in male Dahl S rats and 255 ± 25 mg/day, 129 ± 8 mg/day, and 169 ± 12 mg/day in the 4A-, 4A+, and 4A3,8+ strains, respectively. The antihypertensive and renoprotective effects of transfer of the P4504A region were associated with signficant increases in the expression of P4504A mRNA, P4504A protein levels, and the renal formation of 20-HETE. Interestingly, transfer of the P4504A region had no effect on blood pressure in female rats of the 4A+ or 4A3,8+ congenic strains, but it still reduced the degree of proteinuria and renal injury. These studies exclude the P4504A1 and 4A2 loci as the causal genes in this region in the development of hypertension in Dahl S rats. However, they indicate that the P4504A3 and 4A8 genes still lie in the interval between D5Rat108 and D5Rat54 that contains a locus that reduces blood pressure, is renoprotective, and alters the expression of P4504A genes in Dahl S rats.