Effects of PPAR-ligand-Clofibrate- on NO Production: Role of PKC and PKA

Nitric oxide (NO), an endogenous vasodilator, is a key regulator of basal vascular tone. Peroxisome proliferator activated receptor  (PPAR) ligand, clofibrate, has been reported to increase production of NO. Protein kinases C (PKC), a family of protein kinase enzymes, is involved in controlling the function of proteins through phosphorylation of hydroxyl groups of serine and threonine amino acid residues. Protein kinases A (PKA) is a cAMP-dependent protein kinase. There are evidence in support of clofibrate effect on NO production/availability independent of NO synthesis. Production of NO has been linked to protein kinases PKA and C-mediated signaling mechanisms. Therefore, we postulated that clofibrate-mediated increase in NO production might be attributed to PKA/PKC signaling pathway. We examined clofibrate mediated increase in NO production/availability in renal proximal tubular cells isolated from PPAR knockout (KO) mice and the role of PKA/PKC signaling pathways using PKA 14-22 and chelerythrine, PKA and PKC inhibitors, respectively. Effect of clofibrate on eNOS and iNOS gene/protein expression was examined. Our result indicated reduced NO production in PPAR KO mice compared to the WT. Addition of clofibrate enhanced NO production in both groups, which was abolished by L-NAME. Both PKC and PKA inhibitors reduced clofibrate-mediated NO production in both groups. Clofibrate increased eNOS and iNOS mRNA and iNOS protein expression in the KO but not in WT. Clofibrate did not affect PKA/PKC protein expression in either group. Our data suggest that clofibrate effect on NO production is through induction of iNOS gene and it is PPAR-independent mechanism.

Author(s): Zivar Yousefipour

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