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TGF‐β1 attenuates CFTR‐mediated anion secretion across porcine vas deferens epithelia via the p38 MAPK pathway
Author(s) -
Yi Sheng,
PierucciAlves Fernando,
Schultz Bruce D.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.913.13
Subject(s) - vas deferens , forskolin , secretion , mapk/erk pathway , medicine , endocrinology , chemistry , receptor , cystic fibrosis transmembrane conductance regulator , apical membrane , autocrine signalling , biology , microbiology and biotechnology , signal transduction , epithelium , cystic fibrosis , genetics
This study is designed to identify effects of transforming growth factor β1 (TGF‐β1) on ion transport across vas deferens epithelia. In modified Ussing chambers, PVD9902 cells (derived from porcine vas deferens) that were exposed to TGF‐β1 exhibited attenuated forskolin‐stimulated anion secretion and reduced effects of DASU‐02, a CFTR channel blocker. RT‐PCR and western blots revealed that TGF‐β1 down‐regulates mRNA expression and protein expression of CFTR. Biotinylation assays suggested that TGF‐β1 also reduced the abundance of CFTR in the apical membrane. The effect of TGF‐β1 on anion secretion was abrogated by a TGF‐β1 receptor I inhibitor and was reduced by an inhibitor of p38 MAPK, suggesting that TGF‐β1 interacts with its cognate receptor on vas deferens epithelial cells to activate p38 MAPK signaling. This conclusion was further supported by the observation that TGF‐β1 enhances phospho‐p38 MAPK abundance. Additionally, anisomycin, a p38 MAPK activator, mimicked the effect of TGF‐β1 to reduce forskolin‐stimulated anion secretion. Men harboring profound CFTR mutations exhibit infertility and reproductive duct anomalies, whereas mild mutations have variable presentations. Our observations suggest that TGF‐β1 reduces CFTR‐mediated anion secretion, which would likely compound the effects associated with mild CFTR mutations and would compromise male fertility. [NIH HD058398 and RR017686]