Renal cytochrome P450 as a determinant of impaired natriuresis by PPAR-gamma ligands in ovariectomized obese rats.
OBJECTIVE
Peroxisome proliferator-activated receptor (PPAR)-gamma 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
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-gamma-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-alpha ligand, fenofibrate, a putative inducer of CYP4A, restored not only the impaired sodium excretion but also the downregulated CYP4A expression.


CONCLUSIONS
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-alpha ligands can provide a novel strategy for preventing the PIO-induced sodium retention.
Yoshioka
Kyoko
K
Department of Internal Medicine, Keio University, Tokyo, Japan.
Wakino
Shu
S
Homma
Koichiro
K
Kanda
Takeshi
T
Tatematsu
Satoru
S
Hasegawa
Kazuhiro
K
Sugano
Naoki
N
Ito
Osamu
O
Omata
Ken
K
Saruta
Takao
T
Hayashi
Koichi
K
D000818:Animals; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008024:Ligands; D008297:Male; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010052:Ovariectomy; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D012964:Sodium / Q000652:urine; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000494:pharmacology
D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D019001:Nitric Oxide Synthase; D042926:Cytochrome P-450 CYP4A; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D011345:Fenofibrate; D000077205:Pioglitazone