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Trpc6 knockout protects against renal fibrosis by restraining the CN‑NFAT2 signaling pathway in T2DM mice
1Department of Pharmacology, Grade III Laboratory of National Administration of Traditional Chinese Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China.
Abstract:
Diabetic kidney disease (DKD), one of the common complications of type‑2 diabetes mellitus (T2DM), has become the principal cause of end‑stage kidney disease. Transient receptor potential channel 6 (TRPC6), one of non‑selective cation channels with significant calcium‑permeability, is associated with renal fibrosis. However, the mechanism of TRPC6 in T2DM‑induced renal fibrosis is still not entirely understood. The present study explored the potential mechanism of Trpc6 knockout in T2DM‑induced renal fibrosis in Trpc6 mice. The results showed that Trpc6 knockout inhibited the loss of body weight and the increase of fasting blood glucose (FBG) and significantly improved renal dysfunction and glomerular fibrosis in T2DM mice. The present study also indicated that Trpc6 knockout significantly lowered the expression of phosphorylated (p‑)SMAD2/3, TGF‑β, calcineurin (CN), nuclear factor of activated T‑cell (NFAT)2 and Nod‑like receptor (NLR) 3 inflammasome‑associated proteins. Calcium imaging results revealed that Trpc6 knockdown could decrease the levels of [Ca2+]i and inhibited calcium homeostasis imbalance. Moreover, it was found that knockout of Trpc6 had no significant influence on lipid disposition and reactive oxygen species generation in the kidney cortex. The present study suggested that knockout of Trpc6 may alleviate glomerular fibrosis and delay DKD progression by reducing [Ca2+]i overload and inhibiting the CN‑NFAT2 pathway in T2DM mice.
Insights
Trpc6 knockout significantly improved kidney function and reduced fibrosis in type-2 diabetes mellitus mice. This suggests Trpc6 channel inhibition may be a therapeutic strategy for diabetic kidney disease.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Diabetic kidney disease (DKD) is a major complication of type-2 diabetes mellitus (T2DM).
- Transient receptor potential channel 6 (TRPC6) is implicated in renal fibrosis, but its precise role in T2DM-induced DKD is unclear.
Purpose of the Study:
- To investigate the mechanism of TRPC6 in T2DM-induced renal fibrosis.
- To explore the therapeutic potential of Trpc6 knockout in a T2DM mouse model.
Main Methods:
- Utilized Trpc6 knockout mice subjected to T2DM induction.
- Assessed body weight, fasting blood glucose, renal function, and glomerular fibrosis.
- Measured expression of key fibrotic and inflammatory markers (p-SMAD2/3, TGF-β, CN, NFAT2, NLRP3 inflammasome).
- Performed calcium imaging to evaluate intracellular calcium levels and homeostasis.
Main Results:
- Trpc6 knockout ameliorated weight loss, hyperglycemia, renal dysfunction, and glomerular fibrosis in T2DM mice.
- Knockout significantly reduced levels of p-SMAD2/3, TGF-β, calcineurin (CN), NFAT2, and NLRP3 inflammasome proteins.
- Trpc6 knockdown decreased intracellular calcium ([Ca2+]i) and corrected calcium homeostasis imbalance.
- No significant impact on lipid disposition or reactive oxygen species generation was observed.
Conclusions:
- Trpc6 knockout alleviates glomerular fibrosis and delays DKD progression in T2DM mice.
- This protective effect is mediated by reducing intracellular calcium overload and inhibiting the calcineurin-NFAT2 pathway.
- Targeting TRPC6 represents a potential therapeutic strategy for managing diabetic kidney disease.
