Going with the flow in the kidney

The kidney has a highly dynamic extracellular environment, owing to the flow of the filtered blood (pre-urine) through a tubular system. The epithelial cells lining this tubular system can register these variations in pre-urinary flow rates and initiate the activation of the appropriate signaling pathways, which modulate physiological responses including mineral reabsorption.

One of these pathways is the release of extracellular nucleotides, including adenosine triphosphate (ATP), by the epithelial cells. In contrast to the physiological roles of ATP in the healthy kidney, increased extracellular ATP concentrations are associated with various kidney diseases including autosomal dominant polycystic kidney disease (ADPKD). In ADPKD, fluid-filled cysts are formed within the kidney, but especially the collecting duct of the tubular system might be affected.

Researcher Wouter van Megen, together with the invaluable support of his interns Esra Canki, Vera Wagenaar and Charlotte van Waes, set out to delineate the mechanisms underlying flow-induced ATP release in the collecting duct of the kidney in healthy cells and in a cell model of ADPKD. The research group, led by Joost Hoenderop from the Department of Medical BioSciences, published the results in the FASEB Journal on October 11, 2023.

In their study, the authors used a microfluidic setup to modulate fluid flow over the kidney epithelial cells. This revealed that an increase in fluid flow rates resulted in an increase in extracellular ATP release by both the healthy cells and the ADPKD cells, but that the underlying mechanism was substantially different. While in the healthy the ATP release could not be linked to one ATP release channel, the ADPKD cells showed a predominant involvement of the ATP release channel pannexin-1.

As pannexin-1 has already been linked to cyst progression in ADPKD, these results further suggest that it may be an appealing druggable target. At the moment, the research group is finalizing a follow-up study into the treatment potential of pannexin-1 inhibition in a mouse model of ADPKD in an early stage of the disease. They hope that those results will contribute to determining the optimal treatment strategy for pannexin-1 inhibition in ADPKD.

Read the study here

van Megen WH, Canki E, Wagenaar VHA, van Waes CRMM, Peters DJM, Van Asbeck-Van der Wijst J, Hoenderop JGJ. Fluid shear stress stimulates ATP release without regulating purinergic gene expression in the renal inner medullary collecting duct. FASEB J. 2023 Nov;37(11):e23232. doi: 10.1096/fj.202301434R. PMID: 37819258.