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Dysfunction of TRPV4 channels in the collecting duct‐derived cysts of ARPKD
Author(s) -
Zaika Oleg L,
Mamenko Mykola,
Berrout Jonathan,
OˈNeil Roger G,
Pochynyuk Oleh
Publication year - 2012
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.26.1_supplement.868.2
Subject(s) - trpv4 , cyst , duct (anatomy) , pathology , microbiology and biotechnology , chemistry , biology , medicine , endocrinology , transient receptor potential channel , receptor
Collecting duct (CD) cells adjust water‐electrolyte transport in response to mechanical shear stress. The signaling cascade involves elevations of [Ca2+]i due to activation of the mechano‐sensitive Ca2+‐permeable TRPV4 channels. Impaired mechano‐sensitivity in the CD has been implemented in development of autosomal recessive polycystic kidney disease (ARPKD). Here, we combined direct measurements of [Ca2+]i with IHC in freshly isolated split‐opened collecting ducts of S/D rats and monolayer cyst fragments of the rat model of ARPKD, PCK 453, to explore a role of TRPV4 in patho‐physiology of the disease. Elevated flow increased [Ca2+]i in TRPV4‐dependent manner in individual cells of the CD from S/D rats but not in cyst cells from PCK 453 rats. Unexpectedly, prominent apical localization of TRPV4 was detected with IHC in both split‐opened CD and CD‐derived cysts. Pharmacological stimulation of TRPV4 with highly potent activator, GSK1016790A elicits 4 times greater elevations in [Ca2+]i in normal CD than in cyst cells. Consistently, ATP‐mediated activation of TRPV4 was virtually absent in freshly isolated cyst segments from PCK 453 rats. Therefore, we have concluded that the development of ARPKD, whilst does not alter cellular localization, leads to functional impairment of TRPV4 contributing to disrupted mechano‐sensitivity in the CD‐derived cysts.