Activation of PIEZO1 Attenuates Kidney Cystogenesis In Vitro and Ex Vivo.

Autor:	Fan Q; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA., Hadla M; Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA., Peterson Z; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA., Nelson G; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA., Ye H; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA., Wang X; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA., Mardirossian JM; Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA., Harris PC; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.; Department of Biochemistry and Molecular biology, Mayo Clinic, Rochester, Minnesota, USA., Alper SL; Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston MA, USA., Y S P; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA., Beyder A; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.; Enteric NeuroScience Program (ENSP), Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA., Torres VE; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA., Chebib FT; Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA.
Jazyk:	angličtina
Zdroj:	Kidney360 [Kidney360] 2024 Oct 02. Date of Electronic Publication: 2024 Oct 02.
DOI:	10.34067/KID.0000000598
Abstrakt:	Background: The disruption of calcium signaling associated with polycystin deficiency is a key factor in abnormal epithelial growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Calcium homeostasis can be influenced by mechanotransduction. The mechanosensitive cation channel PIEZO1 has been implicated in sensing intrarenal pressure and regulating urinary osmoregulation, but its role in kidney cystogenesis is unclear. Methods: We hypothesized that altered mechanotransduction contributes to cystogenesis in ADPKD, and that activation of mechanosensitive cation channels could be a therapeutic strategy. Results: We demonstrate that Yoda1, a PIEZO1 activator, increases intracellular calcium and reduces forskolin-induced cAMP levels in mouse inner medullary collecting duct (mIMCD3) cells. Notably, knockout of polycystin-2 attenuated the efficacy of Yoda1 in reducing cAMP levels in mIMCD3 cells. Yoda1 also reduced forskolin-induced mIMCD3 cyst surface area in vitro and cystic index in mouse metanephros ex vivo in a dose-dependent manner. However, collecting duct-specific Piezo1 knockout neither induced cystogenesis in wild-type mice nor altered cystogenesis in the Pkd1RC/RC mouse model. Conclusions: These findings support the potential role of PIEZO1 agonists in mitigating cystogenesis by increasing intracellular calcium and reducing cAMP levels, but the unaltered in vivo cystic phenotype following Piezo1 knockout in the collecting duct suggests possible redundancy in mechanotransductive pathways. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)
Databáze:	MEDLINE
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