The reno-vascular A2B adenosine receptor protects the kidney from ischemia.

Abstract

BACKGROUND:

Acute renal failure from ischemia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischemia are urgently needed. Here, we identified a novel pathway of renal protection from ischemia using ischemic preconditioning (IP).

METHODS AND FINDINGS:

For this purpose, we utilized a recently developed model of renal ischemia and IP via a hanging weight system that allows repeated and atraumatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in gene-targeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in A1(-/-), A2A(-/-), or A3AR(-/-) mice. In contrast, protection from ischemia was abolished in A2BAR(-/-) mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60-6583 dramatically improved renal function and histology following ischemia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bone-marrow chimera conferred kidney protection selectively to renal A2BARs.

CONCLUSIONS:

These results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischemia.

• Authors: Almut Grenz, Hartmut Osswald, Tobias Eckle, Dan Yang, Hua Zhang, Zung Vu Tran, Karin Klingel, Katya Ravid, Holger K Eltzschig
• Journal: PLoS medicine (PLoS Med) Vol. 5 Issue 6 Pg. e137 (Jun 24 2008) ISSN: 1549-1676 [Electronic] United States
• PMID: 18578565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-propyl-8-(4-sulfophenyl)xanthine
• Adenosine A2 Receptor Antagonists
• Aminopyridines
• BAY 60-6583
• Receptor, Adenosine A2B
• Xanthines
• Nitric Oxide
• Adenosine

Topics

• Adenosine (metabolism)
• Adenosine A2 Receptor Antagonists
• Aminopyridines (pharmacology)
• Animals
• Blood Vessels (metabolism)
• Cytoprotection (drug effects, genetics)
• Extracellular Fluid (metabolism)
• Female
• Inflammation (genetics)
• Ischemia (genetics)
• Kidney (blood supply, drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide (metabolism)
• Receptor, Adenosine A2B (genetics, metabolism, physiology)
• Signal Transduction (genetics)
• Xanthines (pharmacology)