Ischaemia-Reperfusion-Induced Kidney Injury : Experimental studies on the effects of caloric restriction, AMPK activator AICAR and α2-adrenoceptor agonists in the rat

Ischaemia-reperfusion (I/R) injury of the kidneys is a common cause of acute kidney injury (AKI). The incidence of AKI among hospitalized patients is between 2-10%, and the mortality rates are high. Currently there is no medication for AKI. The aim of the present study was to increase our knowledge of the pathophysiological mechanisms underlying ischaemic AKI and to identify tentative drug targets for AKI. Using a well-established murine model of kidney I/R injury combined with biochemical, histological and immunohistochemical assessments of kidney damage, we evaluated the potential of three different treatment strategies, namely preconditioning with CR, AMPK activation by AICAR, and α2-adrenoceptor (AR) activation by the α2-AR agonist Dex, and examined their mechanisms of activity at the cellular level. Caloric restriction (CR) is known to increase life span and prevent different diseases in several species. There are some studies indicating that it might prevent also ischaemic injuries. In Study I preconditioning of the kidneys by CR for 2 weeks ameliorates I/R injury induced inflammatory response, oxidative stress and acute tubular necrosis. The renoprotective effects of CR are mediated, at least in part, via induction of SIRT1 expression in the kidney, promotion of autophagy and counteraction of I/R-induced decreases in the expression of eNOS and PGC- 1α. In study II the AMPK activator AICAR ameliorates I/R injury-induced AKI in a dose-dependent manner when given systemically. In study III preconditioning, but not postconditioning, with the centrally acting α2-AR agonist Dex ameliorates I/R injury-induced renal dysfunction, inflammatory response and acute tubular necrosis. In contrast, neither pre- nor postconditioning with the peripheral α2-AR agonist Fado ameliorates kidney I/R injury, suggesting the importance of central α2-ARs. These findings suggest that compounds mimicking the cellular effects of CR, activators of AMPK and centrally acting α2-AR agonists may represent a novel therapeutic approach to treat ischaemic AKI.