PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta.
Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligands, have a central role in insulin sensitization and adipogenesis. It has been reported that TZDs exert protective effects in both diabetic and nondiabetic models of renal disease, although the exact mechanism is not well understood. In particular, only a few studies have reported the renoprotective effects of TZDs in nondiabetic models of tubulointerstitial fibrosis and inflammation. Therefore, we investigated the anti-fibrotic and anti-inflammatory effects of the TZD troglitazone in the mouse model of unilateral ureteral obstruction (UUO). C57BL/6J mice underwent UUO and were studied after 3 and 7 days. Animals were divided into three groups and received control vehicle, troglitazone (150 mg/kg per day) or troglitazone (300 mg/kg per day) by gavage. Kidneys were harvested for morphological, mRNA and protein analysis. Reverse-transcriptase-PCR was used to assess the expression of transforming growth factor-beta1 (TGF-beta1) and the TGF-beta1 type I receptor (TGF beta R-I). Protein expression was assessed by western blotting (TGF beta R-I) and immunostaining (TGF beta R-I, alpha-smooth muscle actin (alpha-SMA), type I collagen (collagen I), F4/80, and proliferating cell nuclear antigen (PCNA)). The expression of alpha-SMA, collagen I, and F4/80 was decreased in mice treated with troglitazone compared with the control group. The numbers of PCNA-positive interstitial cells were decreased in mice treated with troglitazone. TGF-beta1 mRNA and TGF beta R-I mRNA and protein expression were decreased in the group treated with troglitazone compared with the control group. The beneficial effects of troglitazone treatment were also dose dependent. PPAR-gamma agonist significantly reduced TGF-beta and attenuated renal interstitial fibrosis and inflammation in the model of UUO.
Kawai
Toru
T
Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Masaki
Takao
T
Doi
Shigehiro
S
Arakawa
Tetsuji
T
Yokoyama
Yukio
Y
Doi
Toshiki
T
Kohno
Nobuoki
N
Yorioka
Noriaki
N
D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001160:Arterioles / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D024042:Collagen Type I / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D005355:Fibrosis; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000473:pathology*; D047495:PPAR gamma / Q000819:agonists*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*; D000077288:Troglitazone; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology*
D000199:Actins; D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D002839:Chromans; D024042:Collagen Type I; D047495:PPAR gamma; D018125:Receptors, Transforming Growth Factor beta; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077288:Troglitazone