Pannexin-1 mediates fluid shear stress-sensitive purinergic signaling and cyst growth in polycystic kidney disease

Verschuren, E.H.J.; Rigalli, J.P.; Castenmiller, C.; Rohrbach, M.U.; Bindels, R.J.M.; Peters, D.J.M.; ... ; Hoenderop, J.G.J. (2020)

Article / Letter to editor

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.

• ATP
• fluid shear stress
• pannexin-1
• polycystin-1
• purinergic signaling

• All authors: Verschuren, E.H.J.; Rigalli, J.P.; Castenmiller, C.; Rohrbach, M.U.; Bindels, R.J.M.; Peters, D.J.M.; Arjona, F.J.; Hoenderop, J.G.J.
• Date: 2020-05-01
• Journal: FASEB Journal
• Volume: 34
• Issue: 5
• Pages: 6382 - 6398
• DOI: doi:10.1096/fj.201902901R
• Link: https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201902901R