Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells
Yuan-Ji Day, … , Joel Linden, Mark D. Okusa
Yuan-Ji Day, … , Joel Linden, Mark D. Okusa
Published September 15, 2003
Citation Information: J Clin Invest. 2003;112(6):883-891. https://doi.org/10.1172/JCI15483.
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Article Hematology

Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells

Abstract

Activation of A2A adenosine receptors (A2ARs) protects kidneys from ischemia-reperfusion injury (IRI). A2ARs are expressed on bone marrow–derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A2ARs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A2ARs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A2AR-KO, or WT mice to produce GFP→WT, A2A-KO→WT, or WT→WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A2A-KO mice or A2A-KO→WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT→WT chimera. ATL146e reduced the induction of IL-6, IL-1β, IL-1ra, and TGF-α mRNA in WT→WT mice but not in A2A-KO→WT mice. Plasma creatinine was significantly greater in A2A-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A2AR agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells.

Authors

Yuan-Ji Day, Liping Huang, Marcia J. McDuffie, Diane L. Rosin, Hong Ye, Jiang-Fan Chen, Michael A. Schwarzschild, J. Stephen Fink, Joel Linden, Mark D. Okusa

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Figure 1

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Genotyping and phenotyping mice for the A2AR gene. (a) Ethidium bromide–...
Genotyping and phenotyping mice for the A2AR gene. (a) Ethidium bromide–stained PCR amplification products of tail-clip DNA from WT (A2A+/+) and A2A-KO (A2A–/–) mice. The A2A-KO allele was identified by PCR of the inserted neomycin resistance cassette using oligonucleotide primers (see Methods) NEO-F and NEO-R and yielding a 618-bp product. The A2A WT allele was identified by PCR of a portion of the WT A2AR gene that was deleted from the KO construct using primers WT-F and WT-R and yielding a 163-bp band. +/+, WT; +/–, heterozygous; –/–, homozygous A2A-KO. Each lane represents PCR products from individual mice. (b) Immunohistochemical localization of A2AR in mouse forebrain sections. In the WT brain sections (top), dense A2AR-like immunoreactivity is present in the striatum (caudate putamen) and extends through the cell bridges of the striatum (arrow) to the olfactory tubercles on the ventral surface of the brain. In A2A-KO brain (bottom), specific immunoreactivity is completely absent. Scale bar, 1 mm. CPu, caudate putamen; Tu, tubercles; cc, corpus callosum. (c) Effect of ATL146e in A2A-KO mice. A2A-KO mice were subjected to IRI (see Methods). The rise in plasma creatinine after ATL146e was similar to that after vehicle administration (n = 6, not significant). Values are means ± SE.