Protection against Acute Kidney Injury via A1Adenosine Receptor-Mediated Akt Activation Reduces Liver Injury after Liver Ischemia and Reperfusion in Mice
| Autor: | H. Thomas Lee, Sang Won Park, Vivette D. D'Agati, Kevin M. Brown, Mihwa Kim, Sean W. C. Chen |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
Pathology medicine.medical_specialty medicine.drug_class Apoptosis Enzyme-Linked Immunosorbent Assay Mice Transgenic Pharmacology Kidney Nephrectomy Capillary Permeability Mice medicine Animals Humans RNA Messenger Protein kinase B Mice Knockout Liver injury biology Interleukin-6 Receptor Adenosine A1 Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Liver Diseases Lentivirus Acute kidney injury Alanine Transaminase Acute Kidney Injury medicine.disease Adenosine receptor Actins Oncogene Protein v-akt medicine.anatomical_structure Liver Alanine transaminase Creatinine Reperfusion Injury biology.protein Molecular Medicine Reperfusion injury Gastrointestinal Hepatic Pulmonary and Renal |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 333:736-747 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.110.166884 |
| Popis: | 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 A(1) adenosine receptors (A(1)ARs) in AKI. In this study, we determined whether exogenous and endogenous A(1)AR activation protects against AKI with subsequent liver protection after hepatic IR in mice. We found that after hepatic IR A(1) knockout (KO) mice and A(1)AR antagonist-treated A(1) wild-type (WT) mice developed worse AKI and liver injury compared with vehicle-treated A(1)WT mice. Moreover, a selective A(1)AR agonist protected against hepatic IR-induced AKI and liver injury in A(1)WT mice. Renal A(1)AR-mediated kidney protection plays a crucial role in protecting the liver after IR because: 1) selective unilateral renal lentiviral overexpression of human A(1)ARs [enhanced green fluorescent protein (EGFP)-huA(1)AR] in A(1)KO mice protected against both kidney and liver injury sustained after liver IR, 2) removal of the EGFP-huA(1)AR lentivirus-injected kidney from A(1)KO mice abolished both renal and hepatic protection after liver IR, and 3) bilateral nephrectomy before hepatic ischemia abolished the protective effects of A(1)AR activation in A(1)WT mice. Finally, inhibition of Akt, but not extracellular signal-regulated kinase mitogen-activated protein kinase, prevented the kidney and liver protection afforded by A(1)AR agonist treatment. Taken together, we show that endogenous and exogenous activation of renal A(1)ARs protect against liver and kidney injury after liver IR in vivo via pathways involving Akt activation. |
| Databáze: | OpenAIRE |
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