Adenosine Signaling Increases Proinflammatory and Profibrotic Mediators through Activation of a Functional Adenosine 2B Receptor in Renal Fibroblasts

作者：Wilkinson Patrick F^*; Farrell Francis X; Morel Diane; Law William; Murphy Suzanne

来源：Annals of Clinical and Laboratory Science, 2016, 46(4): 339-345.

• Adenosine
• Adenosine receptor 2B
• cAMP
• renal fibroblasts
• fibrosis
• inflammation
• myofibroblasts
• SMA-a

Interstitial renal fibrosis is a major pathophysiological manifestation of patients diagnosed with Chronic Kidney Disease (CKD), Diabetic Nephropathy (DN) and other inflammatory diseases. Adenosine signaling is an innate autocrine and paracrine cellular signaling pathway involving several key mediators that are elevated in the blood and kidneys of patients with DN. In these studies, we hypothesized that extracellular adenosine signals through one or more functional adenosine GPCRs on renal fibroblasts which increases profibrotic and proinflammatory mediators by inducing an activated fibroblast phenotype. Utilizing the renal fibroblast cell line NRK-49F, the presence and relative abundance of adenosine receptors (AR) A(1), A(2A), A(2B), and A(3) were quantified by RT-PCR. Under normal homeostatic conditions, only AR(1) and AR(2B) were detected. The functionality of each receptor was then assessed by receptor specific pharmacological agonism and antagonism and assessed for modulation of the GPCR associated secondary messenger molecule, cyclic adenosine monophosphate (cAMP). Agonism of the AR(2B) receptor resulted in increased intracellular cAMP while agonism of the AR(1) receptor inhibited cAMP modulation. Upon direct agonism of the AR(2B) receptor, transcripts for profibrotic and inflammatory mediators including SMA-alpha, IL-6, TGF-beta, CTGF, and fibronectin were elevated between 2-4 fold. These data indicate that renal fibroblasts express a functional AR(1) receptor that inhibits cAMP upon stimulation, leading to a functional AR(2B) receptor that increases cAMP upon stimulation and also induces an activated fibroblast phenotype resulting in increased fibrotic and inflammatory mediators.

• 出版日期2016-8