Kidney-specific reconstitution of the A1 adenosine receptor in A1 adenosine receptor knockout mice reduces renal ischemia-reperfusion injury.
Genetic deletion of the adenosine A1 receptor (A1AR) increased renal injury following ischemia-reperfusion injury suggesting that receptor activation is protective in vivo. Here we tested this hypothesis by expressing the human-A(1)AR in A(1)AR knockout mice. Renal ischemia-reperfusion was induced in knockout mice 2 days after intrarenal injection of saline or a lentivirus encoding enhanced green fluorescent protein (EGFP) or EGFP-human-A(1)AR. We found that the latter procedure induced a robust expression of the reporter protein in the kidneys of knockout mice. Mice with kidney-specific human-A(1)AR reconstitution had significantly lower plasma creatinine, tubular necrosis, apoptosis, and tubular inflammation as evidenced by decreased leukocyte infiltration, pro-inflammatory cytokine, and intercellular adhesion molecule-1 expression in the kidney following injury compared to mice injected with saline or the control lentivirus. Additionally, there were marked disruptions of the proximal tubule epithelial filamentous (F)-actin cytoskeleton in both sets of control mice upon renal injury, whereas the reconstituted mice had better preservation of the renal tubule actin cytoskeleton, which co-localized with the human-A(1)ARs. Consistent with reduced renal injury, there was a significant increase in heat shock protein-27 expression, also co-localizing with the preserved F-actin cytoskeleton. Our findings suggest that selective expression of cytoprotective A(1)ARs in the kidney can attenuate renal injury.
Kim
Minjae
M
Department of Anesthesiology, Columbia University, New York, NY, USA.
Chen
Sean W C
SW
Park
Sang Won
SW
Kim
Mihwa
M
D'Agati
Vivette D
VD
Yang
Jay
J
Lee
H Thomas
HT
D000199:Actins; D000818:Animals; D003599:Cytoskeleton; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007668:Kidney / Q000737:chemistry; D007674:Kidney Diseases / Q000628:therapy*; D007684:Kidney Tubules; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D043682:Receptor, Adenosine A1 / Q000008:administration & dosage* / Q000172:deficiency / Q000502:physiology; D015427:Reperfusion Injury / Q000628:therapy*
D000199:Actins; D043682:Receptor, Adenosine A1