Relationship between PPARα activation and NO on proximal tubular Na(+ )transport in the rat

BACKGROUND: Nitric oxide (NO) regulates renal proximal tubular (PT) Na(+ )handling through modulation of Na(+)-K(+ )ATPase. Peroxisome Proliferator Activated Receptorα (PPARα), a nuclear transcription factor, is expressed in PTs and has been reported to influence NO generation/activity in renal tissues. This study tested the hypothesis that PPARα interacts with NO and thereby affects renal tubular Na(+ )transport. Urinary excretion of nitrite (UNO(X)V) and Na(+ )(U(Na)V) and PT Na(+ )transport (Na(+)-K(+ )ATPase activity) were determined in rats treated with clofibrate (250 mg/kg i.p) or WY14643 (45 mg/kg; i.p.), a PPARα ligand, 2% NaCl (orally), clofibrate/NaCl, L-NAME, an inhibitor of NO production (100 mg/kg; orally), L-NAME/Clofibrate. RESULTS: Clofibrate or WY14643 increased PPARα expression by 106 ± 7% (p < 0.05) and 113 ± 8% (p < 0.05), respectively. Similarly, clofibrate and WY14643 increased expression of MCAD, a downstream target protein of PPARα by 123 ± 8% (p < 0.05) and 143 ± 8% (p < 0.05), respectively. L-NAME attenuated clofibrate-induced increase in PPARα expression by 27 ± 2% (p < 0.05) but did not affect MCAD expression. UNO(X)V excretion increased 3–4 fold in rats treated with clofibrate, WY14643 or NaCl from 44 ± 7 to 170 ± 15, 144 ± 18 or 132 ± 11 nmol/24 hr, respectively (p < 0.05). Similarly, clofibrate, WY14643 or NaCl elicited a 2–5 fold increase in U(Na)V. L-NAME significantly reduced basal UNO(X)V and U(Na)V and abolished the clofibrate-induced increase. Clofibrate, WY14643, NaCl or clofibrate + NaCl treatment reduced Na(+)-K(+)-ATPase activity in the PT by 89 ± 23, 62 ± 10, 43 ± 9 and 82 ± 15% (p < 0.05), respectively. On the contrary, L-NAME or ODQ, inhibitor of sGC, abolished the inhibition of Na(+)-K(+)-ATPase activity by clofibrate (p < 0.05). Clofibrate either alone or with NaCl elicited ~2-fold increase in the expression of the α1 subunit of Na(+)-K(+ )ATPase in the PT while L-NAME abolished clofibrate-induced increase in Na(+)-K(+ )ATPase expression. CONCLUSION: These data suggest that PPARα activation, through increased NO generation promotes renal excretion of Na(+ )through reduced Na(+)-K(+ )ATPase activity in the PT probably via post translational modification of Na(+)-K(+)-ATPase.