1. Notch3 as a novel therapeutic target for the treatment of ADPKD by regulating cell proliferation and renal cyst development.
- Author
-
Su L, Chen T, Hu H, Xu Z, Luan X, Fu K, Ren Y, Sun D, Sun Y, and Guo D
- Subjects
- Animals, Mice, Humans, Mice, Inbred C57BL, Male, Kidney metabolism, Kidney pathology, Kidney drug effects, Receptor, Notch3 metabolism, Receptor, Notch3 genetics, Cell Proliferation drug effects, Cell Proliferation physiology, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant drug therapy, Polycystic Kidney, Autosomal Dominant pathology, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic kidney disease. Emerging research indicates that the Notch signaling pathway plays an indispensable role in the pathogenesis of numerous kidney diseases, including ADPKD. Herein, we identified that Notch3 but not other Notch receptors was overexpressed in renal tissues from mice with ADPKD and ADPKD patients. Inhibiting Notch3 with γ-secretase inhibitors, which block a proteolytic cleavage required for Notch3 activation, or shRNA knockdown of Notch3 significantly delayed renal cyst growth in vitro and in vivo. Subsequent mechanistic study elucidated that the cleaved intracellular domain of Notch3 (N3ICD) and Hes1 could bind to the PTEN promoter, leading to transcriptional inhibition of PTEN. This further activated the downstream PI3K-AKT-mTOR pathway and promoted renal epithelial cell proliferation. Overall, Notch3 was identified as a novel contributor to renal epithelial cell proliferation and cystogenesis in ADPKD. We envision that Notch3 represents a promising target for ADPKD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF