Renal function and vasomotor activity in mice lacking the Cyp4a14 gene

Abstract

The production of 20-hydroxyeicosatetraenoic acid (20-HETE) in the kidney is thought to be involved in the control of renal vascular tone and tubular sodium and chloride reabsorption. Cytochrome (Cyp) P-450 enzymes of the Cyp4a family in the mouse, namely 4a10, -12 and 14, are involved in 20-HETE synthesis. Recent advances in the molecular genetics of the mouse have produced mice in which Cyp4a isoforms have been disrupted and the consequence of such an approach is examined. This study evaluated the effect of deletion of the Cyp4a14 gene on blood pressure, renal vascular responses and tubular function. When compared with the wild-type (WT) litter mates, systolic blood pressure was greater in Cyp4a14 null (KO) mice as were renal vascular responses to angiotensin II or phenyephrine, G protein-coupled receptor (GPCR) agonists, but not KCl, a non-GPCR agonist. Renal vascular responses to guanosine 5'-O-(gamma-thio)triphosphate, a non-hydrolyzable GTP analog, or NaF(4), an activator of G-proteins, were also enhanced. However, vasodilation to bradykinin or apocynin but not sodium nitroprusside was blunted in Cyp4a14 null (KO) kidneys. These changes in KO mice were accompanied by increased 20-HETE synthesis, reduced renal production of nitric oxide (NO), increased lipid hydroperoxides and increased apocynin-inhibitable vascular NADPH oxidase activity that was prevented by administration of NO synthase (NOS) inhibitor, suggesting endothelial nitric oxide synthase (eNOS) uncoupling. Cyp4a14 KO mice also exhibited a diminished capacity to excrete an acute sodium load (0.9% NaCl, 2.5 mL/kg). These data suggest that deletion of the Cyp4a gene conferred a prohypertensive status via mechanisms involving increased 20-HETE synthesis and eNOS uncoupling leading to increased oxidative stress, enhanced vasoconstriction but diminished vasodilation as well as a defect in the renal excretory capacity in Cyp4a14 KO mice. These mechanisms suggest that the Cyp4a14-deficient mouse may be a useful model for evaluation of NO/20-HETE interactions.