Relationship between PPARalpha 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 Receptor alpha (PPARalpha), 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 PPARalpha interacts with NO and thereby affects renal tubular Na+ transport. Urinary excretion of nitrite (UNOXV) and Na+ (UNaV) 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 PPARalpha 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 PPARalpha 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 PPARalpha by 123 +/- 8% (p < 0.05) and 143 +/- 8% (p < 0.05), respectively. L-NAME attenuated clofibrate-induced increase in PPARalpha expression by 27 +/- 2% (p < 0.05) but did not affect MCAD expression. UNOXV 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 UNaV. L-NAME significantly reduced basal UNOXV and UNaV 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 approximately 2-fold increase in the expression of the alpha1 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 PPARalpha 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.