Abstract
Hepatic ischemia reperfusion (IR) injury causes acute kidney injury (AKI). However, the contribution of AKI to the pathogenesis of liver IR injury is unclear. Furthermore, controversy still exists regarding the role of A1 adenosine receptors (A1ARs) in AKI. In this study, we determined whether exogenous and endogenous A1AR activation protects against AKI with subsequent liver protection after hepatic IR in mice. We found that after hepatic IR A1 knockout (KO) mice and A1AR antagonist-treated A1 wild-type (WT) mice developed worse AKI and liver injury compared with vehicle-treated A1WT mice. Moreover, a selective A1AR agonist protected against hepatic IR-induced AKI and liver injury in A1WT mice. Renal A1AR-mediated kidney protection plays a crucial role in protecting the liver after IR because: 1) selective unilateral renal lentiviral overexpression of human A1ARs [enhanced green fluorescent protein (EGFP)-huA1AR] in A1KO mice protected against both kidney and liver injury sustained after liver IR, 2) removal of the EGFP-huA1AR lentivirus-injected kidney from A1KO mice abolished both renal and hepatic protection after liver IR, and 3) bilateral nephrectomy before hepatic ischemia abolished the protective effects of A1AR activation in A1WT mice. Finally, inhibition of Akt, but not extracellular signal-regulated kinase mitogen-activated protein kinase, prevented the kidney and liver protection afforded by A1AR agonist treatment. Taken together, we show that endogenous and exogenous activation of renal A1ARs protect against liver and kidney injury after liver IR in vivo via pathways involving Akt activation.
Footnotes
This work was supported by the National Institutes of Health [Grant DK58547].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.166884.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- IR
- ischemia reperfusion
- A1AR
- A1 adenosine receptor
- huA1AR
- human A1AR
- AKI
- acute kidney injury
- WT
- wild type
- KO
- knockout
- F-actin
- filamentous actin
- CCPA
- 2-chloro-N6-cyclopentyladenosine
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine
- EGFP
- enhanced green fluorescent protein
- KW-3902
- 8-(noradamantan-3-yl)-1,3-dipropylxanthine
- ERK
- extracellular signal-regulated kinase
- MAPK
- mitogen-activated protein kinase
- PD98059
- 2′-amino-3′-methoxyflavone
- RT-PCR
- reverse transcription-polymerase chain reaction
- ICAM-1
- intercellular adhesion molecule-1
- EBD
- Evans blue dye
- PI3K
- phosphoinositide 3 kinase l
- TUNEL
- terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling
- ALT
- alanine aminotransferase
- TNF-α
- tumor necrosis factor α
- IL-6
- interleukin-6
- KC
- keratinocyte-derived cytokine
- MCP-1
- monocyte chemoattractive protein-1
- MIP-2
- macrophage inflammatory protein-2
- MEK1
- meiosis-specific serine/threonine-protein kinase 1
- Cr
- creatinine
- GAPDH
- glyceraldehyde 3-phosphate dehydrogenase.
- Received February 12, 2010.
- Accepted March 19, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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