Upregulation of renal medullary 20‐HETE production opposes the development of hypertension in Sleeping Beauty Transposon CYP4A1 transgenic Dahl S rats

Abstract

A genetic deficiency in the renal formation of 20‐HETE, reported to reduce sodium transport in the TALH, contributes to the development of hypertension in Dahl S (S) rats. Therefore, we hypothesized that increased expression of CYP4504A protein and renal formation of 20‐HETE attenuates the rise in MAP in S rats. We created a transgenic rat in which the CYP4A1 gene responsible for the production of 20‐HETE was introduced into the S genetic background. We found the production of 20‐HETE in the renal outer medulla was similar in S and CYP4A transgenic rats on standard (0.3%NaCl) chow (8 ±4 vs 10±3 pmol/mg/min). After 28 days on 8%NaCl diet, renal medullary 20‐HETE production increased markedly and was 3‐fold higher in CYP4A1 transgenic animals compared to S rats (127±22 vs 40±16 pmol/mg/min). MAP was significantly lower in the CYP4A1 (n=10) transgenic rats as compared to S rats (139±5 vs 177±10 mmHg, n=8, p<0.05). Protein excretion was significantly lower in CYP4A1 transgenic rats relative to S rats (175±22 vs 295±22 mg/day, p<0.05) and the degree of renal injury was greatly reduced. These results indicate that the renal medullary production of 20‐HETE is elevated on a high salt diet and upregulation of the expression of CYP4A1 gene in the S genetic background increases the renal production of 20‐HETE, improves proteinuria and opposes the development of hypertension. 1T32HL105324‐01, AHA11POST7520052, HL36279, HL29587.