Pioglitazone attenuates diabetic nephropathy 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 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.
Ko
Gang Jee
GJ
Department of Internal Medicine, Korea University Ansan-Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do, 425-020, Korea. cdragn@unitel.co.kr
Kang
Young Sun
YS
Han
Sang Youb
SY
Lee
Mi Hwa
MH
Song
Hye Kyoung
HK
Han
Kum Hyun
KH
Kim
Hyoung Kyu
HK
Han
Jee Young
JY
Cha
Dae Ryong
DR
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D024141:Collagen Type IV / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007333:Insulin Resistance / Q000502:physiology; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000096:biosynthesis; D000077205:Pioglitazone; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011347:Procollagen / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
D018932:Chemokine CCL2; D024141:Collagen Type IV; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D011347:Procollagen; D045162:Thiazolidinediones; C508645:monocyte chemoattractant protein 1 (66-77); D000077205:Pioglitazone