Renal fibrosis is regarded as the final common

Renal fibrosis is regarded as the final common pathway for most forms of progressive renal disease, and mouse UUO is a widely accepted experimental model of renal injury leading to extreme fibrosis localized to the interstitial compartment. A-306989 attenuated the mRNA expression levels of several key markers of fibrosis and inflammation in the UUO model. The highest dose (50mg/kg) also reduced macrophage infiltration. However, A-306989 did not reduce the deposition of interstitial collagen. In contrast, another group has reported that an A2A receptor agonist reduced collagen deposition on days 3 and 7 in C57BL/6 mice, but did not affect interstitial collagen levels on day 14 after UUO injury (Xiao et al., 2013a). The same group also found that Bleomycin A5 hydrochloride of the A2A receptor gene exacerbated interstitial fibrosis on days 3 and 7, but not day on 14 after UUO surgery. The rationale for the lack of effect at the later time point was that the nonreversible injury continued to drive pathological mechanisms, and the renal damage may have been too advanced and severe at this point in the model. Speculatively, the lack of effect of A-306989 in the current study with UUO mice may be related to the severity of the fibrosis and/or the increase in endogenous levels of ADO that result from AK inhibition are not sufficient to reduce the extreme fibrosis. It is to be noted that a caveat to our studies is that we have not specifically measured levels of endogenous level of ADO in various models in vivo following treatment with A-306989 or addressed the contribution of the observed effects at the level of A2R receptor subtypes. In summary, administration of a selective AK inhibitor, A-306989, protected against ex vivo cytoskeletal damage to podocytes following a PAN insult, and reduced proteinuria in both PAN and anti-GBM models of renal injury. Prophylactic A-306989 treatment reduced the expression of several pro-inflammatory/fibrotic genes in PAN-induced nephrosis, but only mRNA for osteopontin was decreased following therapeutic dosing suggesting a key interaction between ADO and this secreted phosphoprotein in regulating renal damage. Macrophage infiltration was reduced by A-306989 in both the anti-GBM and UUO models demonstrating a role for ADO in regulating this pathophysiological response to tissue injury. A-306989 also reduced the mRNA expression of pro-inflammatory/fibrotic genes in UUO mice, collagen deposition was not decreased which may be a consequence of the severity of this model. Most of the effects of A-306989 mimicked the actions observed by A2A receptor agonists that had been previously reported by other groups, and demonstrate that increasing endogenous levels of ADO may be sufficient for renoprotection. Pharmacological enhancement of ADO by using an AK inhibitor may confer advantages over administration of exogenous ADO agonist by limiting undesired ancillary actions.
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