13 April 2021

Joost Hoenderop and other researchers, theme Renal disorders, demonstrated that purinergic signaling and αENaC mRNA expression is controlled by extracellular vesicles flowing along the nephron segments. These findings, published in the FASEB Journal, confirm the regulation of renal purinergic signaling by Extracellular vesicles (EVs), as previously demonstrated in other tissues. Furthermore, the work points to a new role for EVs in intercellular communication in the kidney that may not only affect sodium balance, but also other physiological and pathophysiological processes affected by purinergic signaling.

Purinergic signaling regulates several renal physiological and pathophysiological processes. EVs are nanoparticles released by most cell types, which, in non-renal tissues, modulate purinergic signaling. 

The aim of this study was to investigate the effect of EVs from renal proximal tubule (HK2) and collecting duct cells (HCD) on intra- and intersegment modulation of extracellular ATP levels, the underlying molecular mechanisms, and the impact on the expression of the alpha subunit of the epithelial sodium channel (αENaC). 

HK2 cells were exposed to HK2 EVs, while HCD cells were exposed to HK2 and HCD EVs. Extracellular ATP levels and αENaC expression were measured by chemiluminescence and qRT-PCR, respectively. ATPases in EV populations were identified by mass spectrometry. The effect of aldosterone was assessed using EVs from aldosterone-treated cells and urinary EVs (uEVs) from primary aldosteronism (PA) patients. HK2 EVs downregulated ectonucleoside-triphosphate-diphosphohydrolase-1 (ENTPD1) expression, increased extracellular ATP and downregulated αENaC expression in HCD cells. ENTPD1 downregulation could be attributed to increased miR-205-3p and miR-505 levels. Conversely, HCD EVs decreased extracellular ATP levels and upregulated αENaC expression in HCD cells, probably due to enrichment of 14-3-3 isoforms with ATPase activity. 

Pretreatment of donor cells with aldosterone or exposure to uEVs from PA patients enhanced the effects on extracellular ATP and αENaC expression. The authors demonstrated inter- and intrasegment modulation of renal purinergic signaling by EVs. 

These findings postulate EVs as carriers of information along the renal tubules, whereby processes affecting EV release and/or cargo may impact on purinergically regulated processes.

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