Opposing Effects of Fibroblast-Specific Adenosine A2b Receptor Knockout on Kidney Fibrotic and Inflammatory Gene Programs in Mice With Obstructive Uropathy

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Background The purine nucleoside adenosine has established anti-inflammatory effects whilst also being reported to promote organ fibrosis by signaling through the adenosine A2a and A2b receptors. Objective Here, we examined the consequences of deletion of the adenosine A2b receptor from fibroblasts in mice with obstructive uropathy caused by unilateral ureteral obstruction (UUO). Methods Experiments were performed in C57BL/6N mice after UUO, and in mouse embryonic fibroblasts (MEFs) stimulated with recombinant transforming growth factor-β1 (TGF-β1). Tamoxifen-inducible fibroblast-specific adenosine A2b receptor knockout mice (A2B FibKO ) were generated by breeding Adora2b fl/fl mice with Col1a2 CreER + mice, and these mice were compared with Adora2b fl/fl mice (A2B Ctrl ) 14 days after sham or UUO surgery. Results mRNA levels of Adora2b , the gene that encodes the adenosine A2b receptor, were increased in mice with UUO, and knockdown of Adora2b diminished fibrotic gene upregulation in MEFs. In A2B FibKO mice with UUO, fibroblast-specific adenosine A2b receptor knockout diminished upregulation of mRNA levels of fibrotic genes but increased mRNA indices of kidney inflammation and tubule injury. These gene expression changes were reflected in a numerical but non-significant reduction in interstitial fibrosis, with persistent tubule epithelial programmed cell death and macrophage accumulation. Expression of Adora2a remained expectedly elevated in UUO kidneys. Conclusions The findings illustrate the bidirectional effects of the adenosine A2b receptor in kidney fibrosis and inflammation, and the relatively small consequences of its cell-specific gene deletion, at least in UUO mice. Specific targeting of adenosine receptors to improve outcomes for kidney disease represents a therapeutic challenge.