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PPARgamma agonists inhibit TGF-beta-PKA signaling in glomerulosclerosis

Rong Zou1, Gang Xu, Xiao-cheng Liu

  • 1Department of Nephrology, Wuhan Integrated TCM & Western Medicine Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Acta Pharmacologica Sinica
|December 29, 2009
PubMed
Abstract

Insights

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists suppress mesangial cell activation and collagen accumulation. This renal protection is partly mediated by blocking the TGF-beta/protein kinase A signaling pathway.

Area of Science:

  • Nephrology
  • Cell Biology
  • Pharmacology

Background:

  • Glomerulosclerosis involves mesangial cell (MC) activation and extracellular matrix accumulation.
  • Transforming growth factor-beta (TGF-beta) is a key mediator in glomerulosclerosis.
  • Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown potential in treating kidney disease.

Purpose of the Study:

  • To elucidate the mechanisms by which PPARgamma agonists exert anti-glomerulosclerosis effects in rat MCs.
  • To investigate the role of the TGF-beta signaling pathway in PPARgamma agonist-mediated protection.

Main Methods:

  • Rat MCs were treated with PPARgamma agonists (troglitazone, telmisartan) and TGF-beta.
  • PPARgamma activation was measured using luciferase assays.
  • Protein kinase A (PKA) activity, pCREB, alpha-SMA, and collagen IV levels were assessed via Western blot and confocal microscopy.

Main Results:

  • PPARgamma agonists inhibited TGF-beta-induced PKA activation and pCREB expression.
  • These agonists also suppressed alpha-SMA and collagen IV protein levels by blocking PKA activation.
  • Troglitazone and telmisartan demonstrated significant inhibition of MC activation markers.

Conclusions:

  • PPARgamma ligands effectively suppress TGF-beta-stimulated MC activation and collagen IV accumulation in vitro.
  • The renoprotective effects of PPARgamma agonists are, in part, mediated by inhibiting the TGF-beta/PKA signaling pathway.
  • These findings suggest a therapeutic role for PPARgamma agonists in glomerulosclerosis treatment.

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