Adenosine A_2Areceptor activation and macrophage‐mediated experimental glomerulonephritis

Abstract

In immune-induced inflammation, leukocytes are key mediators of tissue damage. Since A 2A adenosine receptors (A 2A R) are endogenous suppressors of inflammation, we examined cellular and molecular mechanisms of kidney damage to determine whether selective activation of A 2A R will 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-1α/CCL3, RANTES/CCL5, MIP-1β/CCL4, and MCP-1/CCL2 chemokines. The expression of anti-inflammatory cytokines, IL-4 and IL-10, also increased. The mechanism for these antiinflammatory 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 macrophagerelated inflammatory diseases.

Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A2A and A3 receptors

“…Some studies also demonstrated that A 2A receptor activation may cause suppression of the recruitment of T lymphocytes to the lungs [34,35]. Additionally, increased expression of A 2A adenosine receptors has been described in macrophages during the inflammatory process [36] and has been linked to the suppression of macrophage function and inhibition of immune-associated inflammation [36]. Accordingly, our results demonstrated that inosine controls macrophage access to lung compartments via a mechanism involving A 2A receptors.…”

IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II–Induced Muscle Wasting

“…In C2C12 myotubes, treatment with 1 M AngII did not cause an intracellular calcium spike or phosphorylation of extracellular signal-regulated kinase (ERK; a downstream target of AngII), but in C2C12 infected with an adenovirus encoding AT 1 , 17 AngII stimulated a calcium spike and ERK phosphorylation (Supplemental Figure 1). In L6 cells, we found no expression of AT 2 , AT 1A , or AT 1B receptors by ribonuclease protection assay 18,19 ( Figure 1A). By real-time PCR (RT-PCR), we found no detectable AT 1 receptor mRNA in C2C12 cells, a small amount in gastrocnemius muscle (possibly due to vessels within the muscle) and abundant AT 1 receptor mRNA in mouse vein ( Figure 1B).…”

“…Three micrograms of RNA from rat aorta smooth muscle cells and L6 myotubes were used in an RNAse protection assay using the Torrey Pines Biolabs kit (Houston, TX) as described previously. 18,19 Muscle Fiber Size Mouse TA muscles were flash-frozen in embedding medium. Crosssections were fixed in 4% paraformaldehyde at room temperature.…”

Purinergic signalling in the kidney in health and disease

“…Treatment with an adenosine uptake inhibitor attenuates glomerulonephritis in mice [262]. Activation of A 2A receptors has been proposed as a treatment for macrophagemediated experimental glomerulonephritis ( [100]; see also [85]). In experimental mesangial proliferative glomerulonephritis in the rat (anti-Thy-1 model), there is a pronounced mesangial cell proliferative response leading to glomerular hypercellularity.…”