Endocrinol Metab.  2017 Mar;32(1):115-123. 10.3803/EnM.2017.32.1.115.

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

Affiliations
  • 1Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea. kpark@knu.ac.kr mine9240@naver.com
  • 2Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea.
  • 3Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
  • 4Department of Surgery, Keimyung University School of Medicine, Daegu, Korea.
  • 5Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.
  • 6New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.

Abstract

BACKGROUND
Renal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice.
METHODS
We examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study.
RESULTS
Through hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway.
CONCLUSION
The present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.

Keyword

Renal tubulointerstitial fibrosis; Lobeglitazone; Transforming growth factor beta; Unilateral ureteral obstruction
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