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TRPC6 Knockout Alleviates Renal Fibrosis through PI3K/AKT/GSK3B Pathway
An-Bang Sun1,2, Fang-Hua Li3, Lin Zhu1,2
1Department of Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Objective:
Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney damage. Notably, the knockout of transient receptor potential channel 6 (TRPC6) has shown promise in alleviating renal fibrosis. However, the regulatory impact of TRPC6 on renal fibrosis remains unclear.
Methods:
In vivo, TRPC6 knockout (TRPC6-/-) mice and age-matched 129 SvEv (WT) mice underwent unilateral renal ischemia-reperfusion (uIR) injury surgery on the left renal pedicle or sham operation. Kidneys and serum were collected on days 7, 14, 21, and 28 after euthanasia. In vitro, primary tubular epithelial cells (PTECs) were isolated from TRPC6-/- and WT mice, followed by treatment with transforming growth factor β1 (TGFβ1) for 72 h. The anti-fibrotic effect of TRPC6-/- and the underlying mechanisms were assessed through hematoxylin-eosin staining, Masson staining, immunostaining, qRT-PCR, and Western blotting.
Results:
Increased TRPC6 expression was observed in uIR mice and PTECs treated with TGFβ1. TRPC6-/- alleviated renal fibrosis by reducing the expression of fibrotic markers (Col-1, α-SMA, and vimentin), as well as decreasing the apoptosis and inflammation of PTECs during fibrotic progression both in vivo and in vitro. Additionally, we found that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3β) signaling pathway, a pivotal player in renal fibrosis, was down-regulated following TRPC6 deletion.
Conclusion:
These results suggest that the ablation of TRPC6 may mitigate renal fibrosis by inhibiting the apoptosis and inflammation of PTECs through down-regulation of the PI3K/AKT/GSK3β pathway. Targeting TRPC6 could be a novel therapeutic strategy for preventing chronic kidney disease.
Insights
Ablating transient receptor potential channel 6 (TRPC6) reduces kidney fibrosis by decreasing tubular epithelial cell apoptosis and inflammation. This occurs via the down-regulation of the PI3K/AKT/GSK3β pathway, suggesting TRPC6 as a therapeutic target for chronic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Renal fibrosis is a common endpoint for various kidney injuries.
- Transient receptor potential channel 6 (TRPC6) has shown potential in mitigating renal fibrosis, but its regulatory role is not fully understood.
Purpose of the Study:
- To investigate the impact of TRPC6 knockout on renal fibrosis.
- To elucidate the underlying mechanisms by which TRPC6 influences renal fibrosis progression.
Main Methods:
- Utilized unilateral renal ischemia-reperfusion (uIR) injury in TRPC6 knockout (TRPC6-/-) and wild-type (WT) mice.
- Assessed primary tubular epithelial cells (PTECs) from TRPC6-/- and WT mice treated with transforming growth factor β1 (TGFβ1).
- Evaluated fibrotic markers, apoptosis, inflammation, and the PI3K/AKT/GSK3β signaling pathway using histological and molecular techniques.
Main Results:
- TRPC6 expression was elevated in uIR mice and TGFβ1-treated PTECs.
- TRPC6-/- significantly alleviated renal fibrosis, reducing fibrotic markers (Col-1, α-SMA, vimentin), apoptosis, and inflammation in PTECs.
- The PI3K/AKT/GSK3β signaling pathway was down-regulated in TRPC6-ablated models.
Conclusions:
- TRPC6 ablation mitigates renal fibrosis by inhibiting PTEC apoptosis and inflammation.
- Down-regulation of the PI3K/AKT/GSK3β pathway is a key mechanism in TRPC6's anti-fibrotic effect.
- Targeting TRPC6 presents a potential therapeutic strategy for chronic kidney disease prevention.
