Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats.

@article{citeulike:2691473, abstract = {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 PPARgamma 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 PPARgamma agonist, pioglitazone, on the progression of diabetic nephropathy in type 2 diabetic rats. Inflammatory markers including NF-kappaB, 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 PPARgamma 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-kappaB, CCL2, TGFbeta1, PAI-1 and VEGF. In renal tissues, pioglitazone treatment significantly reduced macrophage infiltration and NF-kappaB activation in association with a decrease in type IV collagen, PAI-1, and TGFbeta1 expression. In cultured mesangial cells, pioglitazone-activated endogenous PPARgamma transcriptional activity and abolished high glucose-induced collagen production. In addition, pioglitazone treatment also markedly suppressed high glucose-induced MCP-1 synthesis and NF-kappaB 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.}, address = {1Department of Internal Medicine, Korea University, Ansan City.}, author = {Ko, Gang Jee J. and Kang, Young Sun S. and Han, Sang Youb Y. and Lee, Mi Hwa H. and Song, Hye Kyoung K. and Han, Kum Hyun H. and Kim, Hyoung Kyu K. and Han, Jee Young Y. and Cha, Dae Ryong R. }, citeulike-article-id = {2691473}, doi = {http://dx.doi.org/10.1093/ndt/gfn157}, issn = {1460-2385}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, keywords = {dn, inflammation, pparg, rat}, month = {April}, posted-at = {2008-04-20 02:12:32}, priority = {2}, title = {Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats.}, url = {http://dx.doi.org/10.1093/ndt/gfn157}, year = {2008} }

TY - JOUR ID - citeulike:2691473 L3 - citeulike-article-id:2691473 TI - Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. JF - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association AD - 1Department of Internal Medicine, Korea University, Ansan City. SN - 1460-2385 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 PPARgamma 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 PPARgamma agonist, pioglitazone, on the progression of diabetic nephropathy in type 2 diabetic rats. Inflammatory markers including NF-kappaB, 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 PPARgamma 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-kappaB, CCL2, TGFbeta1, PAI-1 and VEGF. In renal tissues, pioglitazone treatment significantly reduced macrophage infiltration and NF-kappaB activation in association with a decrease in type IV collagen, PAI-1, and TGFbeta1 expression. In cultured mesangial cells, pioglitazone-activated endogenous PPARgamma transcriptional activity and abolished high glucose-induced collagen production. In addition, pioglitazone treatment also markedly suppressed high glucose-induced MCP-1 synthesis and NF-kappaB 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 - dn KW - inflammation KW - pparg KW - rat 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 PY - 2008/04/03/ UR - http://dx.doi.org/10.1093/ndt/gfn157 ER -