Abstract: TH-PO0059
Distinct Roles of Notch Signaling in Collecting Duct Fate Stabilization and Loop of Henle Cystogenesis
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Feng, Yu, Tianjin Medical University, Tianjin, China
- Zheng, Xiangjian, Tianjin Medical University, Tianjin, China
Background
The kidney collecting duct (CD) consists of principal cells (PCs) and intercalated cells (ICs), whose balanced differentiation is essential for water/electrolyte and acid-base homeostasis. Our previous studies identified Foxp1 as a key regulator of IC differentiation. Upstream, Notch2 promotes PC fate while suppressing IC differentiation, but the downstream mechanisms regulating cell identity remain unclear. In addition, the segment-specific effects of aberrant Notch activation in nephron remodeling and cyst formation are poorly understood.
Methods
To investigate downstream Notch signaling in the collecting duct, we performed Ribo-tag RNA-seq using Cdh16Cre; Notch2fl/fl; Rpl22-HA mice to isolate actively translated mRNAs from Notch2-deficient collecting duct cells. Nrarp, identified as a highly responsive candidate, was further evaluated using genetic mouse models. In parallel, a Notch gain-of-function model (Cdh16Cre; NICD2) was generated to assess the effects of constitutive Notch activation on distal nephron remodeling and cyst formation.
Results
Ribo-tag RNA-seq identified Nrarp as a highly Notch-responsive gene in the collecting duct. Although Nrarp is a known negative feedback regulator of Notch signaling, Nrarp deletion alone did not significantly alter the PC/IC ratio under steady-state conditions, suggesting that Nrarp functions primarily as a context-dependent feedback regulator rather than a direct driver of lineage commitment. Its role appears to stabilize PC-IC fate determination when Notch signaling deviates from physiological levels.
Constitutive NICD activation unexpectedly induced rapid renal cyst formation. Lineage tracing and marker analysis demonstrated that these cysts were not mainly derived from the collecting duct lineage but predominantly expressed Loop of Henle markers, including NKCC2. These findings indicate segment-specific sensitivity to Notch dysregulation, with excessive Notch activation in the Loop of Henle promoting cystic remodeling.
Conclusion
Notch signaling exerts distinct functions across renal compartments. In the collecting duct, the Notch-Nrarp axis mainly stabilizes PC-IC lineage identity, whereas aberrant Notch activation in non-collecting duct segments induces severe cystic remodeling. Together, our findings suggest that the Foxp1 pathway governs IC differentiation, while the Notch-Nrarp axis maintains lineage stability and tubular integrity.