TY - JOUR
T1 - Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats
AU - Ko, Gang Jee
AU - Kang, Young Sun
AU - Han, Sang Youb
AU - Lee, Mi Hwa
AU - Song, Hye Kyoung
AU - Han, Kum Hyun
AU - Kim, Hyoung Kyu
AU - Han, Jee Young
AU - Cha, Dae Ryong
N1 - Funding Information:
Acknowledgements. We thank the Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, for provision of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. This work was supported in part by a Korea University grant.
PY - 2008/9
Y1 - 2008/9
N2 - Background. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play a role in insulin sensitivity, lipid metabolism and inflammation. However, the effects of PPARγ agonist on renal inflammation have not been fully examined in type 2 diabetic nephropathy. Methods. In the present study, we investigated the effect and molecular mechanism of the PPARγ agonist, pioglitazone, on the progression of diabetic nephropathy in type 2 diabetic rats. Inflammatory markers including NF-κB, MCP-1 and pro-fibrotic cytokines were determined by RT-PCR, western blot, immunohistochemical staining and EMSA. In addition, to evaluate the direct anti-inflammatory effect of PPARγ agonist, we performed an in vitro study using mesangial cells. Results. Treatment of OLETF rats with pioglitazone improved insulin sensitivity and kidney/body weight, but had a little effect on blood pressure. Pioglitazone treatment markedly reduced urinary albumin and MCP-1 excretion, and ameliorated glomerulosclerosis. In cDNA microarray analysis using renal cortical tissues, several inflammatory and profibrotic genes were significantly down-regulated by pioglitazone including NF-κB, CCL2, TGFβ1, PAI-1 and VEGF. In renal tissues, pioglitazone treatment significantly reduced macrophage infiltration and NF-κB activation in association with a decrease in type IV collagen, PAI-1, and TGFβ1 expression. In cultured mesangial cells, pioglitazone-activated endogenous PPARγ transcriptional activity and abolished high glucose-induced collagen production. In addition, pioglitazone treatment also markedly suppressed high glucose-induced MCP-1 synthesis and NF-κB activation. Conclusions. These data suggest that pioglitazone not only improves insulin resistance, glycaemic control and lipid profile, but also ameliorates renal injury through an anti-inflammatory mechanism in type 2 diabetic rats.
AB - Background. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play a role in insulin sensitivity, lipid metabolism and inflammation. However, the effects of PPARγ agonist on renal inflammation have not been fully examined in type 2 diabetic nephropathy. Methods. In the present study, we investigated the effect and molecular mechanism of the PPARγ agonist, pioglitazone, on the progression of diabetic nephropathy in type 2 diabetic rats. Inflammatory markers including NF-κB, MCP-1 and pro-fibrotic cytokines were determined by RT-PCR, western blot, immunohistochemical staining and EMSA. In addition, to evaluate the direct anti-inflammatory effect of PPARγ agonist, we performed an in vitro study using mesangial cells. Results. Treatment of OLETF rats with pioglitazone improved insulin sensitivity and kidney/body weight, but had a little effect on blood pressure. Pioglitazone treatment markedly reduced urinary albumin and MCP-1 excretion, and ameliorated glomerulosclerosis. In cDNA microarray analysis using renal cortical tissues, several inflammatory and profibrotic genes were significantly down-regulated by pioglitazone including NF-κB, CCL2, TGFβ1, PAI-1 and VEGF. In renal tissues, pioglitazone treatment significantly reduced macrophage infiltration and NF-κB activation in association with a decrease in type IV collagen, PAI-1, and TGFβ1 expression. In cultured mesangial cells, pioglitazone-activated endogenous PPARγ transcriptional activity and abolished high glucose-induced collagen production. In addition, pioglitazone treatment also markedly suppressed high glucose-induced MCP-1 synthesis and NF-κB activation. Conclusions. These data suggest that pioglitazone not only improves insulin resistance, glycaemic control and lipid profile, but also ameliorates renal injury through an anti-inflammatory mechanism in type 2 diabetic rats.
KW - Diabetic nephropathy
KW - Inflammation
KW - Nuclear factor-kappa B
KW - PPARγ agonist
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=56949105387&partnerID=8YFLogxK
U2 - 10.1093/ndt/gfn157
DO - 10.1093/ndt/gfn157
M3 - Article
C2 - 18388116
AN - SCOPUS:56949105387
SN - 0931-0509
VL - 23
SP - 2750
EP - 2760
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 9
ER -
