Characterization of flow-regulated cortical collecting duct endothelin-1 production

Abstract

Collecting duct (CD) endothelin‐1 (ET‐1) is an autocrine inhibitor of Na+ and water reabsorption. Salt or water loading increases CD ET‐1 production; this is likely due, at least in part, to increased tubule fluid flow. The mechanisms by which flow stimulates CD ET‐1 production are incompletely understood. In particular, flow induction of cortical CD (CCD) and inner medullary CD (IMCD) ET‐1 synthesis may occur via different mechanisms. Since flow‐mediated ET‐1 production in IMCD has been more extensively characterized than in the CCD, this study was undertaken to further examine putative signaling pathways involved in flow‐stimulated CCD ET‐1 production. The CD cell line, mpkCCDcl4, was exposed to static or flow (2 dyne/cm2 for 2 h) conditions and ET‐1/GAPDH mRNA levels were assessed. Intracellular Ca2+, Ca2+‐stimulated Ca2+ release, calcineurin, and protein kinase c α/β isoforms were all involved in the ET‐1 flow response. TRPC6, but not other CD‐expressed TRP channels (TRPC3, 4, and 5, or TRPV4) played a role in the ET‐1 flow response. Purinergic signaling pathways and cilia were not involved in the ET‐1 flow response. Based on these and previously published findings, we present a comparison of flow‐stimulated CD ET‐1 production between CCD and IMCD. We suggest that flow‐stimulated CCD ET‐1 production may be more involved in responding to Na+ delivery, while IMCD ET‐1 production may be more responsive to water and solute delivery; the responsible pathways for mediating these effects in the two regions of the CD appear to be substantially distinct from one another.