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Peroxisome proliferator-activated receptor (PPAR)gamma can inhibit chronic renal allograft damage
Eva Kiss1, Zoran V Popovic, Jens Bedke
1Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Abstract:
Chronic inflammation and fibrosis are the leading causes of chronic allograft failure. The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma is a transcription factor known to have antidiabetogenic and immune effects, and PPARgamma forms obligate heterodimers with the retinoid X receptor (RXR). We have reported that a retinoic acid (RAR)/RXR-agonist can potently influence the course of renal chronic allograft dysfunction. In this study, in a Fischer to Lewis rat renal transplantation model, administration of the PPARgamma-agonist, rosiglitazone, independent of dose (3 or 30 mg/kgBW/day), lowered serum creatinine, albuminuria, and chronic allograft damage with a chronic vascular damage score as follows: 35.0 +/- 5.8 (controls) vs. 8.1 +/- 2.4 (low dose-Rosi; P < 0.05); chronic tubulointerstitial damage score: 13.6 +/- 1.8 (controls) vs. 2.6 +/- 0.4 (low dose-Rosi; P < 0.01). The deposition of extracellular matrix proteins (collagen, fibronectin, decorin) was strikingly lower. The expression of transforming growth factor-beta1 was inhibited, whereas that of bone morphogenic protein-7 (BMP-7) was increased. Intragraft mononuclear cells and activated fibroblast numbers were reduced by 50%. In addition, the migratory and proliferative activity of these cells was significantly inhibited in vitro. PPARgamma activation diminished the number of cells expressing the proinflammatory and fibrogenic proteoglycan biglycan. In macrophages its secretion was blocked by rosiglitazone in a predominantly PPARgamma-dependent manner. The combination of PPARgamma- and RAR/RXR-agonists resulted in additive effects in the inhibition of fibrosis. In summary, PPARgamma activation was potently immunosuppressive and antifibrotic in kidney allografts, and these effects were enhanced by a RAR/RXR-agonist.
Insights
PPARgamma activation, using rosiglitazone, significantly reduced kidney allograft damage and fibrosis. Combining it with RAR/RXR agonists further enhanced these antifibrotic and immunosuppressive effects.
Area of Science:
- Immunology
- Nephrology
- Pharmacology
Background:
- Chronic inflammation and fibrosis are primary drivers of chronic allograft failure.
- Nuclear receptors like PPARgamma and RXR play crucial roles in immune regulation and metabolic processes.
- Previous research indicated retinoic acid (RAR)/RXR agonists influence renal allograft dysfunction.
Purpose of the Study:
- To investigate the efficacy of PPARgamma activation, specifically with rosiglitazone, in mitigating chronic kidney allograft dysfunction.
- To assess the impact of PPARgamma activation on inflammation, fibrosis, and cellular activity within the allograft.
- To evaluate the synergistic effects of combining PPARgamma agonists with RAR/RXR agonists.
Main Methods:
- Utilized a Fischer to Lewis rat renal transplantation model.
- Administered the PPARgamma-agonist rosiglitazone at varying doses (3 or 30 mg/kgBW/day).
- Assessed serum creatinine, albuminuria, chronic allograft damage scores, extracellular matrix deposition, and gene expression (TGF-β1, BMP-7).
- Quantified intragraft cell populations (mononuclear cells, fibroblasts) and their in vitro activity.
- Investigated the role of PPARgamma in biglycan expression and secretion in macrophages.
Main Results:
- Rosiglitazone treatment significantly reduced serum creatinine, albuminuria, and chronic allograft damage scores (vascular and tubulointerstitial).
- Extracellular matrix deposition, TGF-β1 expression, and biglycan-expressing cells were markedly decreased.
- BMP-7 expression was increased, while intragraft mononuclear cell and activated fibroblast numbers and activity were reduced.
- Combined PPARgamma and RAR/RXR agonist treatment showed additive antifibrotic effects.
Conclusions:
- PPARgamma activation demonstrates potent immunosuppressive and antifibrotic properties in kidney allografts.
- Rosiglitazone effectively ameliorates chronic allograft dysfunction by reducing inflammation and fibrosis.
- Co-administration with RAR/RXR agonists enhances the therapeutic benefits of PPARgamma activation for kidney allografts.
