Kcnn4/KCa3.1 inhibition blunts polycystic kidney disease progression in mouse models
Guanhan Yao, Almira Kurbegovic, Camila Parrot, William Foley, William Roman, Seth L. Alper, Marie Trudel
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.
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…
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Taxonomy
TopicsGenetic and Kidney Cyst Diseases · Renal and related cancers · Genetic Syndromes and Imprinting