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.
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 diabeticrats. 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 diabeticrats.
Authors: Jorge E Toblli; Gabriel Cao; Jorge F Giani; Margarita Angerosa; Fernando P Dominici; Nestor F Gonzalez-Cadavid Journal: Kidney Blood Press Res Date: 2010-11-11 Impact factor: 2.687
Authors: Patricia M García-García; María A Getino-Melián; Virginia Domínguez-Pimentel; Juan F Navarro-González Journal: World J Diabetes Date: 2014-08-15
Authors: Ian B McKittrick; Yolanda Bogaert; Kristen Nadeau; Janet Snell-Bergeon; Amber Hull; Tao Jiang; Xiaoxin Wang; Moshe Levi; Karen S Moulton Journal: Am J Physiol Renal Physiol Date: 2011-09-14
Authors: K L Raphael; K A Strait; P K Stricklett; B C Baird; K Piontek; G G Germino; D E Kohan Journal: Am J Nephrol Date: 2009-09-24 Impact factor: 3.754