Notch2 Inhibition and Kidney Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Key Points Notch2 activation promotes kidney cyst growth. Silencing Notch2 ameliorated cyst growth in mice with autosomal dominant polycystic kidney disease. Background Notch signaling, a conserved mechanism of cell-to-cell communication, plays a crucial role in regulating cellular processes, such as proliferation and differentiation, in a context-dependent manner. However, the specific contribution of Notch signaling to the progression of polycystic kidney disease (PKD) remains unclear. Methods We investigated the changes in Notch signaling activity (Notch1–4) in the kidneys of patients with autosomal dominant PKD (ADPKD) and two ADPKD mouse models (early and late onset). Multiple genetic and pharmacologic approaches were used to explore Notch2 signaling during kidney cyst formation in PKD. Results Notch2 expression was significantly increased in the kidney tissues of patients with ADPKD and ADPKD mice. Targeted expression of Notch2 intracellular domain in renal epithelial cells resulted in cyst formation and kidney failure in neonatal and adult mice. Mechanistically, Notch2/Hey2 signaling promoted renal epithelial cell proliferation by driving the expression of the E26 transformation–specific homologous factor (Ehf). Depletion of Ehf delayed Notch2 intracellular domain overexpression–induced cyst formation and kidney failure in mice. A gain-of-function mutation in exon 34 of NOTCH2 (c.6426dupT), which caused PKD in patients with Hajdu–Cheney syndrome, accelerated cell growth in cultured human renal epithelial cells by activating HEY2/EHF signaling. Finally, ablation of Notch2 or treatment of a kidney-targeting nanoparticle carrying the liposome/Notch2–small interfering RNA complex, significantly suppressed kidney cyst growth in early-onset ADPKD mice. Conclusions Notch2 signaling promoted kidney cyst growth, partially by upregulating Ehf expression.