# Kcnn4/KCa3.1 inhibition blunts polycystic kidney disease progression in mouse models

## TL;DR

Blocking the KCa3.1 potassium channel with senicapoc slows kidney cyst growth in mouse models of polycystic kidney disease, suggesting a potential new treatment.

## Contribution

The study demonstrates that KCa3.1 inhibition can delay PKD progression and identifies senicapoc as a promising candidate for clinical trials.

## Key findings

- Genetic and pharmacological inhibition of KCa3.1 reduced cyst growth and improved kidney function in mouse models.
- Senicapoc treatment phenocopied the effects of Kcnn4 inactivation, including reduced cell proliferation and fibrosis.
- KCa3.1 inhibition attenuated cAMP and ERK/Myc signaling pathways linked to PKD progression.

## Abstract

The mechanisms underlying cyst growth and progression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remain unresolved. Since cyst expansion requires epithelial salt and water secretion likely involving basolateral membrane K+ recycling, we investigated the role of KCNN4-encoded K+ channel KCa3.1, inhibited by the potent, pharmacospecific, well-tolerated antagonist, senicapoc. We hypothesized that genetic and/or pharmacological inactivation of KCNN4/KCa3.1 would slow PKD progression. KCNN4 was upregulated in kidneys of patients with ADPKD and of mechanistically distinct PKD mouse models. Cyst expansion in Pkd1–/– murine metanephroi was stimulated by KCa3.1 agonist and was prevented/reversed by senicapoc. In rapidly and/or slowly progressive mouse Pkd1 models, Kcnn4 inactivation slowed renal cyst growth; attenuated PKD-stimulated cAMP and ERK/Myc signaling pathways; reduced PKD-associated ciliary elongation, cell proliferation, and fibrosis; improved renal function; and prolonged survival. Importantly, senicapoc treatment of Pkd1 mouse models phenocopied most effects of Kcnn4 inactivation. This first study on the efficacy of KCa3.1 inhibition in PKD progression recommends senicapoc as a clinical trial candidate for ADPKD.

Genetic and pharmacological inhibition of Kcnn4/KCa3.1 prevents or regresses cysts ex vivo, delays polycystic kidney disease in vivo and suggests a clinical trial candidate.