Renal cytochrome P450 as a determinant of impaired natriuresis by PPAR-gamma ligands in ovariectomized obese rats

Objective: Peroxisome proliferator–activated receptor (PPAR)‐ γ ligand, pioglitazone (PIO), is reported to induce edema especially in postmenopausal women. The aim of this study was to elucidate the mechanism for PIO‐induced sodium retention and to discover the therapeutic strategy for the PIO‐induced changes in renal sodium handling. Methods and Procedures: Zucker obese rats were ovariectomized and were given PIO for 8 weeks. Renal sodium excretion and renal expressions of several enzymes that generate natriuretic substances were examined. Results: Sodium excretion was decreased in ovariectomized (OVX) rats that were given PIO when compared with OVX rats that were not. Urinary nitrites/nitrates excretion was decreased in OVX rats, but was restored by PIO. The expressions of nitric oxide synthases (NOSs) and cyclooxygenases‐1/2 (COX‐1/2) were unaltered. Similarly, the expression of epithelial sodium channels (ENaC), identified as a PPAR‐ γ ‐regulated gene product, was unaffected. In contrast, the expression of cytochrome P450 4A (CYP4A) was increased in OVX rats, and was downregulated by PIO. Co‐treatment of OVX rats with PIO and PPAR‐ α ligand, fenofibrate, a putative inducer of CYP4A, restored not only the impaired sodium excretion but also the downregulated CYP4A expression. Discussion: PIO‐induced sodium retention is specific in female OVX rats. Ovariectomy decreases renal NO production, but upregulates renal CYP4A expression to compensate for renal sodium balance. In this setting, PIO downregulates CYP4A, leading to sodium retention. Furthermore, PPAR‐ α ligands can provide a novel strategy for preventing the PIO‐induced sodium retention.