TY - JOUR
T1 - Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys
AU - Schwiebert, Erik M.
AU - Wallace, Darren P.
AU - Braunstein, Gavin M.
AU - King, Sandi R.
AU - Peti-Peterdi, Janos
AU - Hanaoka, Kazushige
AU - Guggino, William B.
AU - Guay-Woodford, Lisa M.
AU - Darwin Bell, P.
AU - Sullivan, Lawrence P.
AU - Grantham, Jared J.
AU - Taylor, Amanda L.
PY - 2002
Y1 - 2002
N2 - ATP and its metabolites are potent autocrine agonists that act extracellularly within tissues to affect epithelial function. In polycystic kidneys, renal tubules become dilated and/or encapsulated as cysts, creating abnormal microenvironments for autocrine signaling. Previously, our laboratory has shown that high-nanomolar to micromolar quantities of ATP are released from cell monolayers in vitro and detectable in cyst fluids from microdissected human autosomal dominant polycystic kidney (ADPKD) cysts. Here, we show enhanced ATP release from autosomal recessive polycystic kidney (ARPKD) and ADPKD epithelial cell models. RT-PCR and immunoblotting for P2Y G protein-coupled receptors and P2X purinergic receptor channels show expression of mRNA and/or protein for multiple subtypes from both families. Assays of cytosolic Ca2+ concentration and secretory Cl- transport show P2Y and P2X purinergic receptor-mediated stimulation of Cl- secretion via cytosolic Ca2+-dependent signaling. Therefore, we hypothesize that autocrine purinergic signaling may augment detrimentally cyst volume expansion in ADPKD or tubule dilation in ARPKD, accelerating disease progression.
AB - ATP and its metabolites are potent autocrine agonists that act extracellularly within tissues to affect epithelial function. In polycystic kidneys, renal tubules become dilated and/or encapsulated as cysts, creating abnormal microenvironments for autocrine signaling. Previously, our laboratory has shown that high-nanomolar to micromolar quantities of ATP are released from cell monolayers in vitro and detectable in cyst fluids from microdissected human autosomal dominant polycystic kidney (ADPKD) cysts. Here, we show enhanced ATP release from autosomal recessive polycystic kidney (ARPKD) and ADPKD epithelial cell models. RT-PCR and immunoblotting for P2Y G protein-coupled receptors and P2X purinergic receptor channels show expression of mRNA and/or protein for multiple subtypes from both families. Assays of cytosolic Ca2+ concentration and secretory Cl- transport show P2Y and P2X purinergic receptor-mediated stimulation of Cl- secretion via cytosolic Ca2+-dependent signaling. Therefore, we hypothesize that autocrine purinergic signaling may augment detrimentally cyst volume expansion in ADPKD or tubule dilation in ARPKD, accelerating disease progression.
KW - Adenosine 5′-triphosphate
KW - Autocrine
KW - Epithelia
KW - Polycystic kidney disease
KW - Purinergic receptors
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U2 - 10.1152/ajprenal.0337.2000
DO - 10.1152/ajprenal.0337.2000
M3 - Article
C2 - 11880338
AN - SCOPUS:0036086838
SN - 0363-6127
VL - 282
SP - F763-F775
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 4 51-4
ER -