Renal tubule necrosis and apoptosis modulation by A1 adenosine receptor expression.
We have shown that A1 adenosine receptors (A1ARs) are cytoprotective against renal tubular necrosis and apoptosis both in vivo and in vitro. To study the role of A1AR numbers on renal epithelial cell survival, we stably overexpressed the human A1 receptor in a porcine renal tubule cell line and utilized primary cultures of proximal tubules obtained from A1AR knockout mice. Receptor-overexpressing cells were protected against peroxide-induced necrosis and tumor necrosis factor-alpha/cycloheximide-induced apoptosis. Conversely, cultured proximal tubule cells from receptor knockout mice showed more necrotic and apoptotic cell loss than corresponding cells from wild-type mice. Overexpression of the receptor resulted in a significantly higher baseline expression of both total and phosphorylated heat-shock protein (HSP)27; the latter due to A1 receptor enhancement of p38 and AP2 mitogen-activated protein kinase activities. The resistance to cell death in the porcine cells was reversed by selective A1 receptor antagonism and by a selective inhibitor of HSP synthesis. Receptor activation in wild-type mice in vivo led to increased total and phosphorylated HSP27, whereas receptor knockout mice showed decreased baseline and adenosine-mediated HSP phosphorylation. These studies show that endogenous A1AR activation produces cytoprotective effects in renal proximal tubules by modulating HSP27 signaling pathways.
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Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032-3784, USA. tl128@columbia.edu
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D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D058916:Adenosine A1 Receptor Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2