PPARα interacts with PHD proteins on Renal Fibrosis in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease

Abstract

Peroxisome proliferator activated receptor (PPAR)α and prolyl hydroxylase domain‐containing protein (PHD), “sensors” of cellular energy and oxygen have protective effects in the kidney and potentially act in a complimentary fashion but the mechanisms involved are not fully known. This study examined the effects of PPARa and its interaction with PHD in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO). UUO increased hydroxyl proline in PPARa WT and KO kidneys (P<0.05) but to a greater extent in KO kidneys. Dimethyl oxallyl glycine (DMOG), a PHD inhibitor, markedly blunted the effect only in WT kidneys (P<0.05). TGFβ expression was also increased (~ 3‐fold, P<0.05) in both WT and KO kidneys. However, DMOG blunted UUO‐induced increase in TGFb expression only in WT kidneys (P<0.05). Bilirubin, an index of heme oxygenase activity, was lower in KO kidneys at basal level (P<0.05) and was reduced in WT kidneys (P<0.05) following UUO but paradoxically increased in KO kidneys (P<0.05). DMOG blunted the reduction in bilirubin in WT (P<0.05) but was without effect in KO kidneys. Serum arginase activity, an index of cellular content of L‐Arginine, was increased in WT mice (P<0.05) but there was no change in KO mice following UUO. DMOG abolished the effect in WT but not KO mice. These data suggest that PPARα plays a protective role against UUO that appears to be coupled to PHD proteins by mechanisms related to heme oxygenase and arginase.Support or Funding InformationThis study was supported by the National Institutes of Health grant G12MD007605.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.