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Inhibition of pannexin-1 does not restore electrolyte balance in precystic Pkd1 knockout mice.

ABSTRACT: Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD), which is characterized by the formation of fluid-filled cysts in the kidney. In a subset of ADPKD patients, reduced blood calcium (Ca²⁺) and magnesium (Mg²⁺) concentrations are observed. As cystic fluid contains increased ATP concentrations and purinergic signaling reduces electrolyte reabsorption, we hypothesized that inhibiting ATP release could normalize blood Ca²⁺ and Mg²⁺ levels in ADPKD. Inducible kidney-specific Pkd1 knockout mice (iKsp-Pkd1^-/-) exhibit hypocalcemia and hypomagnesemia in a precystic stage and show increased expression of the ATP-release channel pannexin-1. Therefore, we administered the pannexin-1 inhibitor brilliant blue-FCF (BB-FCF) every other day from Day 3 to 28 post-induction of Pkd1 gene inactivation. On Day 29, both serum Ca²⁺ and Mg²⁺ concentrations were reduced in iKsp-Pkd1^-/- mice, while urinary Ca²⁺ and Mg²⁺ excretion was similar between the genotypes. However, serum and urinary levels of Ca²⁺ and Mg²⁺ were unaltered by BB-FCF treatment, regardless of genotype. BB-FCF did significantly decrease gene expression of the ion channels Trpm6 and Trpv5 in both control and iKsp-Pkd1^-/- mice. Finally, no renoprotective effects of BB-FCF treatment were observed in iKsp-Pkd1^-/- mice. Thus, administration of BB-FCF failed to normalize serum Ca²⁺ and Mg²⁺ levels.

SUBMITTER: van Megen WH

PROVIDER: S-EPMC10984814 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Inhibition of pannexin-1 does not restore electrolyte balance in precystic Pkd1 knockout mice.

van Megen Wouter H WH van Houtert Teun J TJ Bos Caro C Peters Dorien J M DJM de Baaij Jeroen H F JHF Hoenderop Joost G J JGJ

Physiological reports 20240401 7

Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD), which is characterized by the formation of fluid-filled cysts in the kidney. In a subset of ADPKD patients, reduced blood calcium (Ca2+) and magnesium (Mg2+) concentrations are observed. As cystic fluid contains increased ATP concentrations and purinergic signaling reduces electrolyte reabsorption, we hypothesized that inhibiting ATP release could normalize blood Ca2+ and Mg<su ...[more]

PMID: 38561249

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Inhibition of pannexin-1 does not restore electrolyte balance in precystic Pkd1 knockout mice.

Publications

Inhibition of pannexin-1 does not restore electrolyte balance in precystic Pkd1 knockout mice.

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