Activation of Trpv4 Reduces the Hyperproliferative Phenotype of Cystic Cholangiocytes From an Animal Model of ARPKD

Abstract

Background & Aims-In polycystic liver diseases, cyst formation involves cholangiocyte hyperproliferation. In PCK rats, an animal model of autosomal recessive polycystic kidney disease (ARPKD), decreased [Ca 2+ ] i in cholangiocytes is associated with hyperproliferation. We recently showed Trpv4, a calcium-entry channel, is expressed in normal cholangiocytes and its activation leads to [Ca 2+ ] i increase. Thus, we hypothesized that pharmacological activation of Trpv4 might reverse the hyperproliferative phenotype of PCK cholangiocytes.

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

“…A recent study identifies an antiproliferative role for TRPV4 in cholangiocytes from ARPKD rats and TRPV4 activation has a tendency to decrease liver cysts. 49 This study also provides initial observation that injection of GSK1016790A diminishes renal cyst area. In our study, we manage, for the first time, isolation of monolayers of CD-derived cysts to correlate TRPV4 function, mechanosensitivity of native CD cells, and renal cystogenesis at the timescale of ARPKD progression using per os administration of the TRPV4 activator, GSK1016790A.…”

“…Indeed, a recent report provided initial evidence that prolonged injection of GSK1016790A to PCK453 rats decreases renal cystic area. 49 Therefore, we next tested if GSK1016790A treatment interferes with ARPKD progression by restoring mechanosensitive properties of the CD-derived cyst cells.…”

Discrete Control of TRPV4 Channel Function in the Distal Nephron by Protein Kinases A and C

“…Adequate mechanosensitive [Ca 2ϩ ] i responses are important determinants of many physiological processes in late nephron segments, including flow-dependent K ϩ secretion (15,25), regulatory volume decreases (26), etc. Furthermore, we and others have recently demonstrated that pharmacological stimulation of TRPV4 activity is instrumental for blunting renal cystogenesis in ARPKD models (18,27). In this study, we defined two distinct intracellular signaling cascades separately controlling TRPV4 trafficking and functional activity in murine distal nephrons.…”

Optical Recording Reveals Novel Properties of GSK1016790A-Induced Vanilloid Transient Receptor Potential Channel TRPV4 Activity in Primary Human Endothelial Cells

“…The selective agonist GSK1016790A has been extensively used to study the physiological role of TRPV4 channels (Thorneloe et al, 2008;Xu et al, 2009;Gradilone et al, 2010;Jin et al, 2011;Mihara et al, 2011;Ryskamp et al, 2011). However, little is currently known about how GSK1016790A stimulates TRPV4 channel activity.…”