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

Gang Jee Ko, Young Sun Kang, Sang Youb Han, Mi Hwa Lee, Hye Kyoung Song, Kum Hyun Han, Hyoung Kyu Kim, Jee Young Han, Dae-Ryong Cha

Research output: Contribution to journalArticle

100 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2750-2760
Number of pages11
JournalNephrology Dialysis Transplantation
Volume23
Issue number9
DOIs
Publication statusPublished - 2008 Sep 1

Fingerprint

pioglitazone
Diabetic Nephropathies
Anti-Inflammatory Agents
Peroxisome Proliferator-Activated Receptors
Kidney
Insulin Resistance
Mesangial Cells
Plasminogen Activator Inhibitor 1
Inbred OLETF Rats
Inflammation
Glucose
Collagen Type IV
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Lipid Metabolism
Vascular Endothelial Growth Factor A

Keywords

  • Diabetic nephropathy
  • Inflammation
  • Nuclear factor-kappa B
  • PPARγ agonist
  • Type 2 diabetes

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. / Ko, Gang Jee; Kang, Young Sun; Han, Sang Youb; Lee, Mi Hwa; Song, Hye Kyoung; Han, Kum Hyun; Kim, Hyoung Kyu; Han, Jee Young; Cha, Dae-Ryong.

In: Nephrology Dialysis Transplantation, Vol. 23, No. 9, 01.09.2008, p. 2750-2760.

Research output: Contribution to journalArticle

Ko, Gang Jee ; Kang, Young Sun ; Han, Sang Youb ; Lee, Mi Hwa ; Song, Hye Kyoung ; Han, Kum Hyun ; Kim, Hyoung Kyu ; Han, Jee Young ; Cha, Dae-Ryong. / Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. In: Nephrology Dialysis Transplantation. 2008 ; Vol. 23, No. 9. pp. 2750-2760.
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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

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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

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