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PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta.
Lab Invest. 2009 Jan; 89(1):47-58.LI

Abstract

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.

Authors+Show Affiliations

Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19002105

Citation

Kawai, Toru, et al. "PPAR-gamma Agonist Attenuates Renal Interstitial Fibrosis and Inflammation Through Reduction of TGF-beta." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 89, no. 1, 2009, pp. 47-58.
Kawai T, Masaki T, Doi S, et al. PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Lab Invest. 2009;89(1):47-58.
Kawai, T., Masaki, T., Doi, S., Arakawa, T., Yokoyama, Y., Doi, T., Kohno, N., & Yorioka, N. (2009). PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Laboratory Investigation; a Journal of Technical Methods and Pathology, 89(1), 47-58. https://doi.org/10.1038/labinvest.2008.104
Kawai T, et al. PPAR-gamma Agonist Attenuates Renal Interstitial Fibrosis and Inflammation Through Reduction of TGF-beta. Lab Invest. 2009;89(1):47-58. PubMed PMID: 19002105.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. AU - Kawai,Toru, AU - Masaki,Takao, AU - Doi,Shigehiro, AU - Arakawa,Tetsuji, AU - Yokoyama,Yukio, AU - Doi,Toshiki, AU - Kohno,Nobuoki, AU - Yorioka,Noriaki, Y1 - 2008/11/10/ PY - 2008/11/13/pubmed PY - 2009/2/12/medline PY - 2008/11/13/entrez SP - 47 EP - 58 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab Invest VL - 89 IS - 1 N2 - 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. SN - 1530-0307 UR - https://www.unboundmedicine.com/medline/citation/19002105/PPAR_gamma_agonist_attenuates_renal_interstitial_fibrosis_and_inflammation_through_reduction_of_TGF_beta_ L2 - https://doi.org/10.1038/labinvest.2008.104 DB - PRIME DP - Unbound Medicine ER -