PUBLICATION
Pannexin-1 mediates fluid shear stress-sensitive purinergic signaling and cyst growth in polycystic kidney disease
- 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.
- ID
- ZDB-PUB-200403-32
- Date
- 2020
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34(5): 6382-6398 (Journal)
- Registered Authors
- Arjona, F.J.
- Keywords
- ATP, fluid shear stress, pannexin-1, polycystin-1, purinergic signaling
- MeSH Terms
-
- Adenosine Triphosphate/urine*
- Adult
- Animals
- Calcium/metabolism
- Connexins/genetics
- Connexins/metabolism*
- Cysts/genetics
- Cysts/metabolism
- Cysts/pathology*
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism*
- Polycystic Kidney Diseases/genetics
- Polycystic Kidney Diseases/metabolism
- Polycystic Kidney Diseases/pathology*
- Stress, Mechanical*
- TRPP Cation Channels/physiology*
- Zebrafish
- PubMed
- 32159259 Full text @ FASEB J.
Citation
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. (2020) Pannexin-1 mediates fluid shear stress-sensitive purinergic signaling and cyst growth in polycystic kidney disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 34(5):6382-6398.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping