AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney.
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.
Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
J
J
Lempiäinen
P
P
Finckenberg
J
J
Levijoki
E
E
Mervaala
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003404:Creatinine / Q000097:blood; D008297:Male; D009336:Necrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012265:Ribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D056564:Sirtuin 1 / Q000378:metabolism; D014508:Urea / Q000097:blood
D020011:Protective Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D014508:Urea; D003404:Creatinine; D055372:AMP-Activated Protein Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C031143:AICA ribonucleotide