title: A1 adenosine receptor knockout mice are protected against acute radiocontrast nephropathy in vivo.
abstract: The role of renal A1 adenosine receptors (A1AR) in the pathogenesis of radiocontrast nephropathy is controversial. We aimed to further elucidate the role of A1AR in the pathogenesis of radiocontrast nephropathy and determine whether renal proximal tubule A1AR contribute to the radiocontrast nephropathy. To induce radiocontrast nephropathy, A1AR wild-type (WT) or knockout (KO) mice were injected with a nonionic radiocontrast (iohexol, 1.5-3 g iodine/kg). Some A1WT mice were pretreated with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; a selective A1AR antagonist) before iohexol injection. A1AR contribute to the pathogenesis of radiocontrast nephropathy in vivo as the A1WT mice developed significantly worse acute renal failure, more renal cortex vacuolization, and had lower survival 24 h after iohexol treatment compared with the A1KO mice. DPCPX pretreatment also protected the A1WT mice against radiocontrast-induced acute renal failure. No differences in renal cortical apoptosis or inflammation were observed between A1WT and A1KO mice. To determine whether the proximal tubular A1AR mediate the direct renal cytotoxicity of radiocontrast, we treated proximal tubules in culture with iohexol with or without 2-chloro-N6-cyclopentyladenosine (a selective A1AR agonist) or DPCPX pretreatment. We also subjected cultured proximal tubule cells overexpressing A1AR or lacking A1AR to radiocontrast injury. Iohexol caused a direct dose-dependent reduction in proximal tubule cell viability as well as proliferation. Neither the A1AR agonist nor the antagonist treatment affected proximal tubule viability or proliferation. Moreover, overexpression or lack of A1AR failed to impact the iohexol toxicity on proximal tubule cells. Therefore, we conclude that radiocontrast causes acute renal failure via mechanisms dependent on A1AR; however, renal proximal tubule A1AR do not contribute to the direct tubular toxicity of radiocontrast.
authors.affiliation: Dept. of Anesthesiology, Anesthesiology Research Laboratories, Columbia Univ., College of Physicians and Surgeons, New York, NY 10032-3784, USA. tl128@columbia.edu
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Jan
authors.forename: Soo Chan
authors.initials: SC
authors.lastname: Bae
authors.forename: Jin Deok
authors.initials: JD
authors.lastname: Joo
authors.forename: Farida R
authors.initials: FR
authors.lastname: Goubaeva
authors.forename: Jay
authors.initials: J
authors.lastname: Yang
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003287:Contrast Media / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D007472:Iohexol; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D043682:Receptor, Adenosine A1 / Q000172:deficiency* / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D003287:Contrast Media; D043682:Receptor, Adenosine A1; D014970:Xanthines; D007472:Iohexol; C051360:1,3-dipropyl-8-cyclopentylxanthine