AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney

Abstract

BACKGROUND AND PURPOSE Renal ischaemia/reperfusion (RI/R) injury is a major cause of acute kidney injury (AKI) and an important determinant of long‐term kidney dysfunction. AMP‐kinase and histone deacetylase sirtuin 1 (SIRT1) regulate cellular metabolism and are activated during hypoxia. We investigated whether AMP‐kinase activator AICAR (5‐amino‐4‐imidazolecarboxamide riboside‐1‐β‐D‐ribofuranoside) ameliorates RI/R injury and whether SIRT1 is involved in the pathogenesis. EXPERIMENTAL APPROACH Eight‐week‐old Sprague Dawley rats were divided into five groups: (i) sham‐operated group; (ii) I/R group (40 min bilateral ischaemia followed by 24 h of reperfusion; (iii) I/R group + AICAR 50 mg·kg−1 i.v. given 60 min before operation; (iv). I/R group + AICAR 160 mg·kg−1 i.v; (v) I/R group + AICAR 500 mg·kg−1 i.v. Serum creatinine and urea levels were measured. Acute tubular necrosis (ATN), monocyte/macrophage infiltration and nitrotyrosine expression were scored. Kidney AMP‐activated protein kinase (AMPK) and SIRT1 expressions were measured. KEY RESULTS Highest dose of AICAR decreased serum creatinine and urea levels, attenuated I/R injury‐induced nitrosative stress and monocyte/macrophage infiltration, and ameliorated the development of ATN. Kidney I/R injury was associated with decreased AMPK phosphorylation and a fivefold increase in kidney SIRT1 expression. AICAR increased pAMPK/AMPK ratio and prevented the I/R‐induced increase in renal SIRT1 expression. CONCLUSIONS AND IMPLICATIONS AICAR protects against the development of ATN after kidney I/R injury. Activators of kidney AMP kinase may thus represent a novel therapeutic approach to patients susceptible to AKI and to those undergoing kidney transplantation. The present study also suggests a role for SIRT1 in the pathogenesis of RI/R injury.

Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney

“…In line with our concept, it was shown in cultured mouse proximal tubular cells subjected to various forms of metabolic stress that genetic or pharmacologic inhibition of AMPK caused apoptosis. Furthermore, in rats subjected to renal ischemia/reperfusion injury, application of a high dose of AMPK activator AICAR shortly before ischemia significantly improves cell survival (40). Cytc purified from ischemic kidney is dephosphorylated (not shown), similar to Cytc isolated from ischemic brain (41).…”

Stanniocalcin-1 Inhibits Renal Ischemia/Reperfusion Injury via an AMP-Activated Protein Kinase-Dependent Pathway

“…15 Thus, effective protection by STC1 requires preexposure of the cells to STC1 or preactivation of AMPK. 21 Indeed, Tg overexpression of STC1 (pre-exposure) inhibits ROS and renal I/R injury in mice 16 ; AMPK activity is elevated in STC1 Tg mice at baseline (relative to WT) and does not change after I/R ( Figure 7A). In contrast, STC1 KO mice are more susceptible to I/R kidney injury (relative to WT); consistently, AMPK activity is low in STC1 KO mice at baseline and does not change after I/R (Figure 9).…”

“…30 AMPK regulates cellular metabolism, and recent studies suggest that pretreatment with AMPK activators (5-aminoimidazol-4-carboxamide-1-b-d-ribofuranoside and metformin) may protect from I/R injury. 20,21,31 To determine whether AMPK is important for protection from I/R kidney injury and test whether STC1 acts upstream of AMPK, we pretreated WT mice with CC before I/R. Pretreatment with CC decreased I/R-induced activation of AMPK by one half, compared with responses in vehicle-pretreated mice ( Figure 2).…”

“…19,20 Recent studies suggest that pretreatment with AMPK activators (5-aminoimidazol-4-carboxamide-1-b-d-ribofuranoside and metformin) may have a protective role in renal I/R injury. 21 We, therefore, hypothesized that STC1 protects from I/R through activation of AMPK.…”

Place de l’AMP-activated protein kinase dans le préconditionnement ischémique rénal

“…De façon similaire, une é tude ré cente utilisant un modè le d'isché mie brè ve et ré pé té e du membre infé rieur avant une I/R ré nale chez le rat a dé montré que les mé canismes tissulaires et cellulaires impliqué s dans le PCI diffè rent d'un organe à un autre, selon l'espè ce animale et le protocole expé rimental [25]. Plus ré cemment, deux groupes indé pendants ont suggé ré que la pré activation pharmacologique de l'AMPK in vivo par metformine ou par AICAR protè ge les reins des dommages causé s par un é pisode d'I/R [10,39]. Les travaux de Seo-Mayer et al montrent, dans un modè le d'isché mie (30 minutes)/reperfusion (48 heures) chez la souris, que l'administration intrapé ritoné ale de metformine (300 mg/kg par jour) pendant 3 jours avant clampage des pé dicules vasculaires ré naux pré serve l'architecture des cellules tubulaires et la distribution membranaire de la pompe Na + /K + -ATPase.…”