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.

Kidney ischemia-reperfusion (I/R) injury is a common cause of acute kidney injury. We tested whether dexmedetomidine (Dex), an alpha2 adrenoceptor (α2-AR) agonist, protects against kidney I/R injury. Sprague–Dawley rats were divided into four groups: (1) Sham-operated group; (2) I/R group (40 min ischemia followed by 24 h reperfusion); (3) I/R group + Dex (1 μg/kg i.v. 60 min before the surgery), (4) I/R group + Dex (10 μg/kg). The effects of Dex postconditiong (Dex 1 or 10 μg/kg i.v. after reperfusion) as well as the effects of peripheral α2-AR agonism with fadolmidine were also examined. Hemodynamic effects were monitored, renal function measured, and acute tubular damage along with monocyte/macrophage infiltration scored. Kidney protein kinase B, toll like receptor 4, light chain 3B, p38 mitogen-activated protein kinase (p38 MAPK), sirtuin 1, adenosine monophosphate kinase (AMPK), and endothelial nitric oxide synthase (eNOS) expressions were measured, and kidney transciptome profiles analyzed. Dex preconditioning, but not postconditioning, attenuated I/R injury-induced renal dysfunction, acute tubular necrosis and inflammatory response. Neither pre- nor postconditioning with fadolmidine protected kidneys. Dex decreased blood pressure more than fadolmidine, ameliorated I/R-induced impairment of autophagy and increased renal p38 and eNOS expressions. Dex downregulated 245 and upregulated 61 genes representing 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in particular, integrin pathway and CD44. Ingenuity analysis revealed inhibition of Rac and nuclear factor (erythroid-derived 2)-like 2 pathways, whereas aryl hydrocarbon receptor (AHR) pathway was activated. Dex preconditioning ameliorates kidney I/R injury and inflammatory response, at least in part, through p38-CD44-pathway and possibly also through ischemic preconditioning.

Aim: We investigated whether preconditioning with caloric restriction (CR) ameliorates kidney ischaemia/reperfusion (I/R) injury and whether the salutary effects of CR are mediated through enhanced autophagy and/ or activation of key metabolic sensors SIRT1, AMP-kinase and PGC-1a. Methods: Six-to seven-week-old Wistar rats were divided into three groups: (i) sham-operated group; (ii) I/R group (40-min ischaemia followed by 24 h of reperfusion); and (iii) I/R group kept under CR (energy intake 70%) for 2 weeks before surgery. In additional experiments, sirtinol and 3-methyladenine (3-MA) were used as inhibitors of SIRT1 and autophagy respectively. Renal function was measured, and acute tubular damage and nitrotyrosine expression were scored. Kidney adenosine monophosphateactivated kinase (AMPK), SIRT1, eNOS, PGC-1a and LC-3B expressions were measured. Results: Caloric restriction improved renal function, protected against the development of acute tubular necrosis and attenuated I/R-induced nitrosative stress. Kidney I/R injury decreased eNOS and PGC-1a expression, inhibit autophagy and increased SIRT1 and AMPK expressions by 2.6-and fourfold respectively. However, phosphorylation level of AMPK was decreased. As compared with I/R injury group, CR further increased kidney SIRT1 expression by 1.8-fold, promoted autophagy and counteracted I/R-induced decreases in the expression of eNOS and PGC-1a. 3-MA abolished the renoprotective effects of CR, whereas sirtinol did not influence renal function in CR rats with I/R injury. Conclusions: Caloric restriction ameliorates acute kidney I/R injury through enhanced autophagy and counteraction of I/R-induced decreases in the renal expression of eNOS and PGC-1a.

Abstract-Angiotensin II (Ang II) induces mitochondrial dysfunction. We tested whether Ang II alters the "metabolomic"profile. We harvested hearts from 8-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGRs) and controls (Sprague-Dawley), all with or without Ang II type 1 receptor (valsartan) blockade. We used gas chromatography coupled with time-of-flight mass spectrometry to detect 247 intermediary metabolites. We used a partial least-squares discriminate analysis and identified 112 metabolites that differed significantly after corrections (false discovery rate q Ͻ0.05). We found great differences in the use of fatty acids as an energy source, namely, decreased levels of octanoic, oleic, and linoleic acids in dTGR (all PϽ0.01). The increase in cardiac hypoxanthine levels in dTGRs suggested an increase in purine degradation, whereas other changes supported an increased ketogenic amino acid tyrosine level, causing energy production failure. The metabolomic profile of valsartan-treated dTGRs more closely resembled Sprague-Dawley rats than untreated dTGRs. Mitochondrial respiratory chain activity of cytochrome C oxidase was decreased in dTGRs, whereas complex I and complex II were unaltered. Mitochondria from dTGR hearts showed morphological alterations suggesting increased mitochondrial fusion. Cardiac expression of the redox-sensitive and the cardioprotective metabolic sensor sirtuin 1 was increased in dTGRs. Interestingly, valsartan changed the level of 33 metabolites and induced mitochondrial biogenesis in Sprague-Dawley rats. Thus, distinct patterns of cardiac substrate use in Ang II-induced cardiac hypertrophy are associated with mitochondrial dysfunction. The finding underscores the importance of Ang II in the regulation of mitochondrial biogenesis and cardiac metabolomics, even in healthy hearts. represents an adaptive and compensatory response to increased workload and represents an independent risk factor of cardiovascular events. Patients with LVH have more strokes, congestive heart failure, and sudden cardiac death compared with those without LVH. 1 The mechanisms are unknown, although angiotensin (Ang) II contributes greatly to the process. Other than the regulatory effects on blood pressure, sodium excretion, and aldosterone secretion, Ang II also induces inflammatory responses and oxidative stress by blood pressure-independent mechanisms. 2-4 Energy metabolism is deranged in LVH, with and without heart failure. 5,6 All 3 of the components of cardiac energy metabolism, namely substrate use, oxidative phosphorylation, and high-energy phosphate metabolism, are affected. Mitochondria generate energy, regulate apoptosis, and produce reactive oxygen species (ROS). Doughan et al 7 showed recently that Ang II induces mitochondrial dysfunction via a protein kinase C-dependent pathway that activates NADPH oxidase and formation of peroxynitrite. Several factors regulate mitochondrial function and biogenesis. ROS, NO, peroxisome proliferatoractivated receptor-␥ coactivator (PGC)...