TRPC6 channels modulate the response of pancreatic stellate cells to hypoxia

Nielsen, Nikolaj; Kondratska, Kateryna; Ruck, Tobias; Hild, Benedikt; Kovalenko, Ilya; Schimmelpfennig, Sandra; Welzig, Jana; Sargin, Sarah; Lindemann, Otto; Christian, Sven; Meuth, Sven; Prevarskaya, Natalia; Schwab, Albrecht
December 2017
Pflugers Archiv European Journal of Physiology;Dec2017, Vol. 469 Issue 12, p1567
Academic Journal
Pancreatic cancer is characterized by a massive fibrosis (desmoplasia), which is primarily caused by activated pancreatic stellate cells (PSCs). This leads to a hypoxic tumor microenvironment further reinforcing the activation of PSCs by stimulating their secretion of growth factors and chemokines. Since many of them elicit their effects via G-protein-coupled receptors (GPCRs), we tested whether TRPC6 channels, effector proteins of many G-protein-coupled receptor pathways, are required for the hypoxic activation of PSCs. Thus far, the function of ion channels in PSCs is virtually unexplored. qPCR revealed TRPC6 channels to be one of the most abundant TRPC channels in primary cultures of murine PSCs. TRPC6 channel function was assessed by comparing PSCs from TRPC6 mice and wildtype (wt) littermates. Cell migration, Ca signaling, and cytokine secretion were analyzed as readout for PSC activation. Hypoxia was induced by incubating PSCs for 24 h in 1% O or chemically with dimethyloxalylglycine (DMOG). PSCs migrate faster in response to hypoxia. Due to reduced autocrine stimulation, TRPC6 PSCs fail to increase their rate of migration to the same level as wt PSCs under hypoxic conditions. This defect could not be overcome by the stimulation with platelet-derived growth factor. In line with these results, calcium influx is increased in wt but not TRPC6 PSCs under hypoxia. We conclude that TRPC6 channels of PSCs are major effector proteins in an autocrine stimulation pathway triggered by hypoxia.


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