Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC‐1α–eNOS pathway and enhanced autophagy

Abstract

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.

Autophagy and the Kidney: Implications for Ischemia-Reperfusion Injury and Therapy

“…[2][3][4][8][9][10][11][13][14][15] However, suppressed autophagy has also been observed in 2 rat models subjected to 40 minutes of warm renal ischemia (Table 1). 6,12 After 48 hours of cold ischemia, autophagy is increased. 16 Regardless of its dynamics (increased or decreased), the role of autophagy after renal IRI is a major matter of debate, with both protective and detrimental properties proposed (Table 1).…”

“…1 Because kidney cells rely heavily on autophagy, an evolutionarily conserved intracellular degradation pathway, for their homeostasis and survival during IRI, stimulation of autophagy harbors therapeutic potential. [2][3][4][5][6] By recycling damaged and toxic cytoplasmic material into new cellular building blocks, autophagy supports antistress responses and energy maintenance. Therefore, it seems logical to reinforce this natural protective mechanism to diminish IRI.…”

“…7 However, paradoxically, autophagy also promotes renal IRI (Table 1). [2][3][4][5][6][8][9][10][11][12][13][14][15][16][17] Consequently, the exact role of autophagy in renal IRI needs to be clarified to determine whether autophagy stimulation or inhibition best attenuates IRI. 18 This is particularly important because many drugs applied in the context of AKI (diuretics) or kidney transplantation (immunosuppressants) influence autophagy and therefore affect renal IRI.…”

Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy

“…8) (114). FoxO transcription factors have been found to also induce PGC-1a transcription, and PGC-1a induction has been associated with increased autophagy (14,99,132,151,177). However, little data are available on this issue and, by contrast, some of them also suggest that during catabolic conditions high PGC-1a levels prevent the excessive activation of proteolytic systems by inhibiting the transcriptional activity of FoxO3 (18).…”

Acute kidney injury

“…This supports the idea of Nrf2 as the mediator of the renoprotective effect of Ipre and Ipost. In addition, caloric restriction enhances the cellular adaption to hypoxia via Sirt1 pathway, provides protection against acute tissue injury and improves survival and kidney function after acute IRI (Mitchell et al 2010, Lempi€ ainen et al 2013. The hypoxic environment of the renal medulla renders it extremely vulnerable to changes in blood flow and oxygen supply (Liu et al 2013).…”