Arachidonic acid (AA) metabolites derived from cytochrome P450 enzymes regulate vascular tone and renal tubular function. The cytochrome P450 4A (Cyp4A) enzymes are responsible for the synthesis of 20- hydroxyeicosatetraenoic (20-HETE), the most abundantly produced AA Cyp P450 metabolite in the kidney. Cyp4a expression and the production of 20-HETE, have been implicated in the development of hypertension. Here we have investigated the expression of various renal isoforms of Cyp4A in a mouse model of mineralocorticoid induced hypertension. This model develops a 30 mmHg rise over 15 days compared to controls there was also a progressive rise in renal weight, (significant by day 13) but not heart weight. We have also tested whether bezafibrate, an inducer of Cyp4a metabolism and PPARα agonist, affected the development of hypertension in this model.
Male C57BL6 mice were uninephrectomised, infused with aldosterone (750 μg aldosterone/kg/day by mini pump for up to 21 days) and were fed a diet containing 1% Na. At days 6,13 and 21, kidneys and blood samples of mice (n=6) were collected for analysis, including in situ hybridisation. In the kidney, by real-time PCR we found a 3-fold increase in Cyp4a14 (P<0.01) and a significant early decrease in Cyp4a12 (P<0.001) as HT develops. Here also, we describe for the first time, a fourth isoform which showed significant down-regulation compared with controls (P<0.001). To induce 20 HETE production, a treatment group were injected with bezafibrate (50 mg/kg/day i.p.), controls were injected with vehicle over the hypertensive time course. Strikingly the bezafibrate treatment prevented the expected rise in BP (n=6, 113±3 mmHg) present in mDOCA mice (n=6, 134±2 mmHg).
These studies make the novel observation that Cyp4a metabolism and PPAR pathways in the development and maintenance of hypertension especially when there is salt sensitivity as in mDOCA mice.
01 - 05 Apr 2006
European Society of Endocrinology