Protection against Acute Kidney Injury via A₁Adenosine Receptor-Mediated Akt Activation Reduces Liver Injury after Liver Ischemia and Reperfusion in Mice

Abstract

Hepatic ischemia reperfusion (IR) injury causes acute kidney injury (AKI). However, the contribution of AKI to the pathogenesis of liver IR injury is unclear. Furthermore, controversy still exists regarding the role of A 1 adenosine receptors (A 1 ARs) in AKI. In this study, we determined whether exogenous and endogenous A 1 AR activation protects against AKI with subsequent liver protection after hepatic IR in mice. We found that after hepatic IR A 1 knockout (KO) mice and A 1 AR antagonisttreated A 1 wild-type (WT) mice developed worse AKI and liver injury compared with vehicle-treated A 1 WT mice. Moreover, a selective A 1 AR agonist protected against hepatic IR-induced AKI and liver injury in A 1 WT mice.

Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver

“…Accumulated evidence suggests that A1R play a role in the protection from I/R injury in several organs such as heart, brain, and lung [12][13][14][26][27][28][29][30][31][32][33][34][35][36][37] through mechanisms that remain to be defined. The present study suggests that A1R activation prevents I/R injury through the control of OXPHOS efficiency.…”

“…Activation of A1R has been shown to protect liver from I/R injury via pathways involving Akt [13]. Taking into account that activated Akt decreases GSK-3β activity, which is related with modulation of the MPT, we probed if the protective effect of preconditioning against hepatic I/R injury involves the activation of the Akt/GSK-3β signaling pathway to prevent mitochondria-mediated I/R injury.…”

“…Furthermore, IPC decreases liver injury after both warm and cold I/R [2,4,9,10]. Several mechanisms have been proposed for protection by IPC, including activation of adenosine receptors [11][12][13][14], increased nitric oxide production [15], activation of protein kinase C [16], up-regulation of heat shock proteins, and increased antioxidant capacity [17,18]. Probably, the process better established to be associated with decrease tolerance to I/R injury is the inability to restore energetic balance following I/R [1,19,20].…”

“…However, it is largely unknown how A1R impact on mitochondrial mechanisms recruited to implement preconditioning. Both ischemic and pharmacological PC enhance Akt phosphorylation and its translocation to mitochondria [13,38,39]. In mitochondria, Akt can phosphorylate glycogen synthase kinase-3β (GSK-3β) on serine 9 causing its inactivation [38,40].…”

Purinergic signalling in the liver in health and disease

“…This is likely mediated by transcription factor Sp1 and is a potential therapeutic target for the treatment of liver ischaemia [117]. This also has renal implications as well, as one study demonstrated that activation of renal A 1 receptors was protective for the liver as well as kidney after liver ischaemia reperfusion injury [198].…”