Abstract
In young rats, ischemic preconditioning (IPC), which consists of 4 cycles of ischemia and reperfusion alleviated kidney injury caused by 40-min ischemia. However,old rats lost their ability to protect the ischemic kidney by IPC. A similar aged phenotype was demonstrated in 6-month-old OXYS rats having signs of premature aging. In the kidney of old and OXYS rats, the levels of acetylated nuclear proteins were higher than in young rats, however, unlike in young rats, acetylation levels in old and OXYS rats were further increased after IPC. In contrast to Wistar rats, age-matched OXYS demonstrated no increase in lysosome abundance and LC3 content in the kidney after ischemia/reperfusion. The kidney LC3 levels were also lower in OXYS, even under basal conditions, and mitochondrial PINK1 and ubiquitin levels were higher, suggesting impaired mitophagy. The kidney mitochondria from old rats contained a population with diminished membrane potential and this fraction was expanded by IPC. Apparently, oxidative changes with aging result in the appearance of malfunctioning renal mitochondria due to a low efficiency of autophagy. Elevated protein acetylation might be a hallmark of aging which is associated with a decreased autophagy, accumulation of dysfunctional mitochondria, and loss of protection against ischemia by IPC.
Highlights
Aging is accompanied by ischemia-associated pathologies and important protective anti-ischemic measures are ischemic preconditioning (IPC) and post conditioning[13,14,15] including both direct and remote[16], shown for a large number of organs and tissues[17,18,19,20], including the kidney[21,22]
The studies of signaling pathways involved in IPC21,23,24 showed that mitochondria are an essential requisite for implementation of protective mechanisms and dysfunction of these organelles may be related with age-dependent changes in the efficiency of IPC25
IPC (4 cycles of 15 seconds of ischemia and 15 seconds of reperfusion each) prior to I/R had a beneficial effect on blood flow restoration (Fig. 1)
Summary
Aging is accompanied by ischemia-associated pathologies and important protective anti-ischemic measures are ischemic preconditioning (IPC) and post conditioning[13,14,15] including both direct and remote[16], shown for a large number of organs and tissues[17,18,19,20], including the kidney[21,22]. The use of old animals is coupled with objective difficulties, and an important challenge is to find models that examine the phenomenon of aging in vivo. One such model is accelerated-senescence OXYS rats. It can be assumed that the accelerated aging affects kidney, making these rats a unique model for studying the effects of ageing on renal diseases. It is unknown whether the protective effect of IPC is sustained in the kidney during advanced ageing. The goal of this study is to analyze possible changes in natural ischemic tolerance mechanisms in the aged kidney with special attention to protein acetylation, lysosomes and components of mitochondrial autophagy
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