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Adenosine A_2A receptor activation and macrophage-mediated experimental glomerulonephritis

Gabriela E. Garcia^*,1, Luan D. Truong^,, Ping Li^*, Ping Zhang^*, Jie Du^*, Jiang-Fan Chen and Lili Feng^*,2

^* Department of Medicine, Section of Nephrology, and

Department of Pathology, Baylor College of Medicine, Houston, Texas, USA;

The Methodist Hospital, Houston, Texas, USA; and

Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA

¹Correspondence: Department of Medicine, Nephrology Section, Alkek N520, One Baylor Plaza, Houston TX, 77030, USA. E-mail: geg{at}bcm.tmc.edu

In immune-induced inflammation, leukocytes are key mediators of tissue damage. Since A_2A adenosine receptors (A_2ARs) are endogenous suppressors of inflammation, we examined cellular and molecular mechanisms of kidney damage to determine if selective activation of A_2AR would suppress inflammation in a rat model of glomerulonephritis. Activation of A_2AR reduced the degree of kidney injury in both the acute inflammatory phase and the progressive phase of glomerulonephritis. This protection against acute and chronic inflammation was associated with suppression of the glomerular expression of the MDC/CCL22 chemokine and down-regulation of MIP-1/CCL3, RANTES/CCL5, MIP-1β/CCL4, and MCP-1/CCL2 chemokines. The expression of anti-inflammatory cytokines, interluekin (IL)-4 and IL-10, also increased. The mechanism for these anti-inflammatory responses to the A_2AR agonist was suppression of macrophages function. A_2AR expression was increased in macrophages, macrophage-derived chemokines were reduced in response to the A_2AR agonist, and chemokines not expressed in macrophages did not respond to A_2AR activation. Thus, activation of the A_2AR on macrophages inhibits immune-associated inflammation. In glomerulonephritis, A_2AR activation modulates inflammation and tissue damage even in the progressive phase of glomerulonephritis. Accordingly, pharmacological activation of A_2AR could be developed into a novel treatment for glomerulonephritis and other macrophage-related inflammatory diseases.—Garcia, G. E., Truong, L. D., Li, P., Zhang, P., Du, J., Chen, J. F., Feng, L. Adenosine A_2A receptor activation and macrophage-mediated experimental glomerulonephritis.

Key Words: chemokines • anti-inflammatory cytokines • tissue injury protection