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Suppression of TRPM2 reduces renal fibrosis and inflammation through blocking TGF-β1-regulated JNK activation

Ying Wang1, Lingwei Chen1, Kangyao Wang1

  • 1Department of Nephropathy, Wenling First People's Hospital of Zhejiang, Wenling, 317500, China.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|October 27, 2019
PubMed

Insights

Targeting TRPM2 (Transient receptor potential melastatin-2) shows promise in treating kidney disease. Inhibiting TRPM2 reduces renal fibrosis and inflammation by blocking JNK signaling pathways, offering a new therapeutic strategy for chronic kidney disease.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pathology

Background:

  • Chronic kidney disease (CKD) is a leading cause of mortality, characterized by renal fibrosis and inflammation.
  • The precise molecular mechanisms driving CKD progression remain incompletely understood.
  • Transient receptor potential melastatin-2 (TRPM2) has emerged as a potential therapeutic target due to its diverse cellular functions.

Purpose of the Study:

  • To investigate the role of TRPM2 in the development of renal fibrosis and inflammation in the context of CKD.
  • To explore the therapeutic potential of TRPM2 inhibition in ameliorating kidney injury.

Main Methods:

  • Utilized a mouse model of unilateral ureteral obstruction (UUO) to induce kidney injury.
  • Assessed renal histological changes using H&E and PAS staining.
  • Measured serum creatinine, blood urea nitrogen (BUN), KIM-1, and Nephrin levels.
  • Analyzed the expression of fibrotic markers (TGF-β1, α-SMA, CTGF, FN, Col1α1) and inflammatory factors.
  • Investigated the involvement of IκBα/NF-κB and JNK signaling pathways.

Main Results:

  • TRPM2 expression was significantly upregulated in kidneys following UUO.
  • TRPM2-deficient mice exhibited markedly alleviated renal histological damage and improved renal function compared to wild-type mice.
  • TRPM2 ablation attenuated renal interstitial fibrosis by downregulating TGF-β1 and associated fibrotic genes.
  • Suppression of TRPM2 reduced inflammatory cell infiltration and pro-inflammatory cytokine release.
  • TRPM2 deficiency inhibited both IκBα/NF-κB and JNK signaling pathways.
  • In vitro studies confirmed that blocking JNK activation suppressed TGF-β1-induced fibrosis and inflammation.

Conclusions:

  • TRPM2 plays a critical role in promoting renal fibrosis and inflammation in response to kidney injury.
  • Inhibition of TRPM2 offers a protective effect against UUO-induced renal damage.
  • TRPM2 may exert its effects by modulating TGF-β1 and subsequently activating JNK signaling.
  • Targeting TRPM2 presents a promising therapeutic strategy for managing CKD.
Keywords:
Chronic kidney diseaseFibrosis and inflammationJNKTGF-β1TRPM2

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