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Pannexin‐1 mediates fluid shear stress‐sensitive purinergic signaling and cyst growth in polycystic kidney disease
Author(s) -
Verschuren Eric H. J.,
Rigalli Juan P.,
Castenmiller Charlotte,
Rohrbach Meike U.,
Bindels René J. M.,
Peters Dorien J. M.,
Arjona Francisco J.,
Hoenderop Joost G. J.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902901r
Subject(s) - pannexin , polycystic kidney disease , purinergic receptor , pkd1 , mechanosensation , microbiology and biotechnology , purinergic signalling , v atpase , chemistry , medicine , extracellular , kidney , endocrinology , biology , connexin , intracellular , gap junction , biochemistry , atpase , receptor , enzyme , adenosine receptor , agonist , ion channel
Abstract Tubular ATP release is regulated by mechanosensation of fluid shear stress (FSS). Polycystin‐1/polycystin‐2 (PC1/PC2) functions as a mechanosensory complex in the kidney. Extracellular ATP is implicated in polycystic kidney disease (PKD), where PC1/PC2 is dysfunctional. This study aims to provide new insights into the ATP signaling under physiological conditions and PKD. Microfluidics, pharmacologic inhibition, and loss‐of‐function approaches were combined to assess the ATP release in mouse distal convoluted tubule 15 (mDCT15) cells. Kidney‐specific Pkd1 knockout mice (iKsp‐ Pkd1 −/− ) and zebrafish pkd2 morphants ( pkd2 ‐MO) were as models for PKD. FSS‐exposed mDCT15 cells displayed increased ATP release. Pannexin‐1 inhibition and knockout decreased FSS‐modulated ATP release. In iKsp‐ Pkd1 −/− mice, elevated renal pannexin‐1 mRNA expression and urinary ATP were observed. In Pkd1 −/− mDCT15 cells, elevated ATP release was observed upon the FSS mechanosensation. In these cells, increased pannexin‐1 mRNA expression was observed. Importantly, pannexin‐1 inhibition in pkd2 ‐MO decreased the renal cyst growth. Our results demonstrate that pannexin‐1 channels mediate ATP release into the tubular lumen due to pro‐urinary flow. We present pannexin‐1 as novel therapeutic target to prevent the renal cyst growth in PKD.