A Self-Reinforcing LGR5-Wnt/β-Catenin-Nedd4L Circuit Drives Fibrotic Progression in Diabetic Kidney Disease - PubMed
10 hours ago
- #fibrosis
- #Wnt signaling
- #diabetic kidney disease
- A self-reinforcing circuit involving LGR5, Wnt/β-catenin, and Nedd4L drives tubulointerstitial fibrosis in diabetic kidney disease.
- LGR5, upregulated in diabetic kidneys, amplifies Wnt signaling by stabilizing Wnt receptors, while the E3 ligase Nedd4L normally degrades LGR5.
- In DKD, activated β-catenin/TCF4 transcriptionally represses Nedd4L, creating a feed-forward loop that maintains high LGR5 levels and persistent Wnt/β-catenin activation.
- This loop promotes nuclear β-catenin translocation and expression of fibrotic mediators like Snail and fibronectin, exacerbating renal fibrosis.
- Disrupting the circuit by restoring Nedd4L or knocking down LGR5 attenuated renal fibrosis in experimental models, suggesting potential therapeutic strategies.