Adenosine A2A receptor activation and macrophage-mediated experimental glomerulonephritis.
In immune-induced inflammation, leukocytes are key mediators of tissue damage. Since A(2A) adenosine receptors (A(2A)Rs) are endogenous suppressors of inflammation, we examined cellular and molecular mechanisms of kidney damage to determine if selective activation of A(2A)R would suppress inflammation in a rat model of glomerulonephritis. Activation of A(2A)R 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-1alpha/CCL3, RANTES/CCL5, MIP-1beta/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(2A)R agonist was suppression of macrophages function. A(2A)R expression was increased in macrophages, macrophage-derived chemokines were reduced in response to the A(2A)R agonist, and chemokines not expressed in macrophages did not respond to A(2A)R activation. Thus, activation of the A(2A)R on macrophages inhibits immune-associated inflammation. In glomerulonephritis, A(2A)R activation modulates inflammation and tissue damage even in the progressive phase of glomerulonephritis. Accordingly, pharmacological activation of A(2A)R could be developed into a novel treatment for glomerulonephritis and other macrophage-related inflammatory diseases.
Garcia
Gabriela E
GE
Department of Medicine, Nephrology Section, Alkek N520, One Baylor Plaza, Houston TX, 77030, USA. geg@bcm.tmc.edu
Truong
Luan D
LD
Li
Ping
P
Zhang
Ping
P
Du
Jie
J
Chen
Jiang-Fan
JF
Feng
Lili
L
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D016207:Cytokines; D043705:Receptor, Adenosine A2A