PPARgamma agonists exert antifibrotic effects in renal tubular cells exposed to high glucose.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. We recently demonstrated that PPARgamma agonists limit high glucose-induced inflammation in a model of proximal tubular cells (PTC; Panchapakesan U, Pollock CA, and Chen XM. Am J Physiol Renal Physiol 287: F528-F534, 2004). However, the role of PPARgamma in the excess extracellular matrix production is largely unknown. We evaluated the effect of 24- to 48-h 8 microM l-805645 or 10 microM pioglitazone on 25 mM D-glucose-induced markers of fibrosis in HK-2 cells. High D-glucose induced nuclear binding of activator protein-1 (AP-1) to 140.8 +/- 10.9% (P < 0.05), which was attenuated with L-805645 and pioglitazone to 82.3 +/- 14.4 (P < 0.01 vs. high D-glucose) and 99.3 +/- 12.2% (P < 0.05 vs. high D-glucose), respectively. High D-glucose increased total production of transforming growth factor (TGF)-beta(1) 139.6 +/- 6.5% (P < 0.05), which was reversed with L-805645 and pioglitazone to 68.73 +/- 5.7 (P < 0.01 vs. high D-glucose) and 112 +/- 13.6% (P < 0.05 vs. high D-glucose). L-805645 and pioglitazone reduced high d-glucose-induced fibronectin from 156.0 +/- 24.9 (P < 0.05) to 81.9 +/- 16.0 and 57.4 +/- 12.7%, respectively (both P < 0.01 vs. high D-glucose). Collagen IV was not induced by high d-glucose. L-805645 and pioglitazone suppressed collagen IV to 68.0 +/- 14.5 (P < 0.05) and 46.5 +/- 11.6% (P < 0.01) vs. high D-glucose, respectively. High D-glucose increased the nuclear binding of NF-kappaB to 167 +/- 22.4% (P < 0.05), which was not modified with PPARgamma agonists. In conclusion, PPARgamma agonists exert antifibrotic effects in human PTC in high glucose by attenuating the increase in AP-1, TGF-beta(1), and the downstream production of the extracellular matrix protein fibronectin.
Panchapakesan
U
U
Dept. of Medicine, University of Sydney, Royal North Shore Hospital, NSW 2065, Australia.
Sumual
S
S
Pollock
C A
CA
Chen
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X
D018929:Cell Culture Techniques; D049109:Cell Proliferation; D005355:Fibrosis / Q000517:prevention & control; D005947:Glucose / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation; D007333:Insulin Resistance; D007668:Kidney / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology*; D050356:Lipid Metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D007004:Hypoglycemic Agents; D047495:PPAR gamma; C508960:TGFB1 protein, human; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005947:Glucose; D000077205:Pioglitazone