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    • Adenosine A A agonists have been shown

    2023-02-01

    Adenosine A2A agonists have been shown to significantly reduce albuminuria in diabetic mice as well as plasma creatinine [24]. Proteinuria was greater in diabetic A2A knock-out (KO) mice than diabetic wild type (WT) mice [24]. Consistent with these findings, our laboratory initially found that proteinuria was significantly higher in diabetic A2A KO mice than diabetic WT mice (proteinuria was 248±8mg/day after 10 weeks of streptozotocin-induced diabetes in A2A KO mice vs. 185±6mg/day in diabetic WT mice, P<0.05). The elevation in proteinuria in diabetic A2A KO mice was also associated with a 50% increase in renal ICAM-1 Genomic DNA Isolation Kit when compared to diabetic WT mice suggesting that A2A receptor stimulation contributes to kidney protection in diabetes via reduction in renal inflammation similar to what has been shown in kidney ischemia–reperfusion injury [37]. The elevation in proteinuria in diabetic A2A KO mice did not seem to be attributed to any significant increase in blood glucose and blood pressure (data are not shown). Adenosine is known to be released in response to inflammation to provide a compensatory anti-inflammatory effect via up-regulation of A2A receptor [25], [36], [38]. Consistent with these findings, our data showed that diabetes down-regulated adenosine kinase, suggesting increased adenosine availability, and up-regulated renal A2A receptor expression without changing A1 receptor expression compared to control. However, the current study suggests that inhibition of adenosine kinase provides renal protection against diabetic insult independent on A2A receptor up-regulation as ABT702 lowered A2A receptor expression and partially restored the decrease in adenosine kinase expression in diabetic mice kidney. Our finding is consistent with the previous finding of Elsherbiny et al. in which adenosine kinase expression decreased and A2A receptor expression increased in diabetic retina and ABT702 treatment reversed these changes [25]. Since previous studies reported increases in glomerular and urinary adenosine levels in diabetic rat [39], our data suggest that during the inflammatory condition of diabetes, adenosine kinase is down-regulated to increase extracellular adenosine levels whereas A2A receptor is up-regulated to mediate adenosine anti-inflammatory properties. Since adenosine kinase inhibition provides renal protection and reduces renal inflammation, these effects would offset the necessity to up-regulate renal A2A receptor expression to combat diabetes-induced renal inflammation. Albuminuria is considered the earliest clinical indicator of diabetic renal injury and marked elevation of albuminuria correlates with the progression of renal disease [40], [41]. In our study, adenosine kinase inhibition with ABT702 significantly reduced the increase in albuminuria in diabetic mice, which we initially thought, is due to reduction in glomerular injury and podocyte loss. Since nephrin and podocalyxin are crucial complex proteins in the assembly and reinforcement of the slit diaphragm in the kidney [42], [43], assessment of nephrin and podocalyxin excretion levels could reflect glomerular injury and podocyte loss. We and others have previously demonstrated a reduction in nephrin expression in diabetic human and streptozotocin-induced diabetic rat and mice models [12], [21], [41]. A2A receptor agonist has been shown to restore podocin and nephrin expression in diabetes [24]; however, in our study adenosine kinase inhibition decreased A2A receptor expression in both control as well as in diabetic mice and did not significantly reduce nephrin and podocalyxin excretion in diabetic mice. Accordingly it is less likely that the reno-protective effect of ABT702 is attributed to the improvement in slit diaphragm protein in the kidney. The extracellular adenosine levels are mainly regulated by intracellular adenosine kinase activity since adenosine degradation to inosine, by adenosine deaminase, has been previously shown to play a minor role in the regulation of adenosinergic function [44]. The mechanism(s) by which adenosine kinase inhibition reduce(s) renal injury in streptozotocin-induced diabetic renal injury is/are not known; however, we could speculate that increased adenosine levels via adenosine kinase inhibition may directly improve glucose homeostasis since previous studies suggest that adenosine agonists improve glucose homeostasis in diabetic animal models [45], [46]. Although we observed a significant reduction in blood glucose levels in ABT702-treated diabetic vs. untreated diabetic mice, the reduction in blood glucose levels is less likely to be the sole reno-protective mechanism of ABT702 in diabetic mice as blood glucose remained significantly higher than control.