title: Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats.
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.
authors.affiliation: Department of Internal Medicine, Korea University Ansan-Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do, 425-020, Korea. cdragn@unitel.co.kr
authors.forename: Gang Jee
authors.initials: GJ
authors.lastname: Ko
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Kang
authors.forename: Sang Youb
authors.initials: SY
authors.lastname: Han
authors.forename: Mi Hwa
authors.initials: MH
authors.lastname: Lee
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Song
authors.forename: Kum Hyun
authors.initials: KH
authors.lastname: Han
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Han
authors.forename: Dae Ryong
authors.initials: DR
authors.lastname: Cha
mesh_terms: 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
chemical_list: 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