A Self-Reinforcing LGR5–Wnt/β-Catenin–Nedd4L Circuit Drives Fibrotic Progression in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a major cause of end-stage renal failure, driven by tubulointerstitial fibrosis. While persistent Wnt/β-catenin signaling promotes fibrosis, its sustained activation mechanism was unclear. This study, using DKD patient samples, db/db mice, and Nedd4L knockout models combined with molecular techniques, identified a key pathogenic circuit. LGR5, upregulated in diabetic kidneys, amplifies Wnt signaling by stabilizing Wnt receptors. The E3 ligase Nedd4L counteracts this by targeting LGR5 for degradation. Crucially, in DKD, the activated β-catenin/TCF4 complex transcriptionally represses Nedd4L, creating a self-reinforcing feedback loop that maintains high LGR5 levels and perpetual Wnt/β-catenin activation. This loop promotes nuclear translocation of β-catenin and expression of fibrotic mediators like Snail and fibronectin. Disrupting this circuit by restoring Nedd4L or knocking down LGR5 attenuated renal fibrosis in experimental models. Thus, the LGR5-Wnt-Nedd4L feed-forward circuit is a key driver of fibrosis in DKD, suggesting Nedd4L restoration or LGR5 inhibition as potential therapeutic strategies. Article Highlights This study was undertaken to explain why Wnt/β-catenin signaling stays persistently active in diabetic kidney disease tubules. This study aimed to determine whether LGR5 amplifies Wnt signaling and whether Nedd4L controls LGR5 stability via ubiquitination. This study found a feed-forward loop: Wnt induces LGR5, LGR5 limits RNF43-receptor interactions to stabilize Wnt receptors, and β-catenin/TCF4 represses Nedd4L to reduce LGR5 ubiquitination. This LGR5-Wnt-Nedd4L circuit represents a targetable mechanism to dampen Wnt signaling and renal fibrosis in diabetic kidney disease.