AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney

Br J Pharmacol. 2012 Jul;166(6):1905-15. doi: 10.1111/j.1476-5381.2012.01895.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Aminoimidazole Carboxamide / therapeutic use
  • Animals
  • Creatinine / blood
  • Male
  • Necrosis / drug therapy
  • Necrosis / metabolism
  • Necrosis / pathology
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Ribonucleotides / pharmacology
  • Ribonucleotides / therapeutic use*
  • Sirtuin 1 / metabolism
  • Urea / blood


  • Protective Agents
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Urea
  • Creatinine
  • AMP-Activated Protein Kinases
  • Sirt1 protein, rat
  • Sirtuin 1
  • AICA ribonucleotide