Aged kidney: can we protect it? Autophagy, mitochondria and mechanisms of ischemic preconditioning

Jankauskas, Stanislovas S.; Silachev, D. N.; Andrianova, Nadezda V.; Pevzner, Irina B.; Zorova, Ljubava D.; Popkov, Vasily A.; Plotnikov, Egor Y.; Zorov, Dmitry B.

doi:10.1080/15384101.2018.1482149

Cited by 22 publications

(13 citation statements)

References 165 publications

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“…However, clinical results for this technique vary considerably between studies [34][35][36], perhaps reflecting the need for further optimization of the procedure, as well as the differences in the study populations [37]. It has been argued that the method is less effective in the elderly [38], who represent the major group of risk for AKI [5,39]. In this context, a pharmacological nephroprotective approach remains a desirable goal, which, unfortunately, is yet to be fully realized.…”

Section: Discussionmentioning

confidence: 99%

The role of PAK1 in the sensitivity of kidney epithelial cells to ischemia-like conditions

2019

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Kidney ischemia, characterized by insufficient supply of oxygen and nutrients to renal epithelial cells, is the main cause of acute kidney injury and an important contributor to mortality world-wide. Earlier research implicated a G-protein coupled receptor (NK1R) in the death of kidney epithelial cells in ischemia-like conditions. P21-associated kinase 1 (PAK1) is involved in signalling by several G-proteins. We explored the consequences of PAK1 inhibition for cell survival under the conditions of reduced glucose and oxygen. Inhibition of PAK1 by RNA interference, expression of a dominant-negative mutant or treatment with small molecule inhibitors greatly reduced the death of cultured kidney epithelial cells. Similar protection was achieved by treating the cells with inhibitors of MEK1, in agreement with the prior reports on PAK1-MEK1 connection. Concomitant inhibition of NK1R and PAK1 offered no better protection than inhibition of NK1R alone, consistent with the two proteins being members of the same pathway. Furthermore, NK1R, PAK and MEK inhibitors reduced the induction of TRAIL in ischemia-like conditions. Considering the emerging role of TRAIL in ischemia-mediated cell death, this phenomenon may contribute to the protective effects of these small molecules. Our findings support further exploration of PAK and MEK inhibitors as possible agents to avert ischemic kidney injury. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

The role of PAK1 in the sensitivity of kidney epithelial cells to ischemia-like conditions

2019

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“…The downregulated genes in aging kidney were enriched in mitochondrial and metabolic processes based on our mRNA sequencing data. Dysregulated mitochondrial functioning has been widely studied in aging kidneys 42 . RNAseq data suggests that Tfam mRNA levels are decreased in aging kidney, which we have verified by RT-QPCR determination.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Wang

Myakala

Libby

et al. 2019

Preprint

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ABSTRACTBackgroundA gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR).MethodsA pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. In addition, 21-month-old mice were treated with a STING inhibitor for 3 weeks.ResultsRemarkably, only an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression.ConclusionsOur studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.Significance StatementThere is an increasing need for prevention and treatment strategies for age-related kidney disease. The hallmarks of aging kidneys are decreased mitochondrial function and increased inflammation. The expression of the nuclear hormone receptors estrogen-related receptors (ERRs) are decreased in aging human and mouse kidneys. This paper investigates the role of ERRs in the aging kidney. Treatment of aging mice with a pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING signaling pathways. Treatment of aging mice with a STING inhibitor decreased inflammation and increased mitochondrial gene expression. These findings identify ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

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“…Similar results were obtained earlier in mice [ 44 ]. This data suggests that lysosomal dysfunction rather than a decrease in autophagosome biogenesis occurs within advanced age [ 24 ]. However, we evaluated some abnormality in the biogenesis of autophagosomes in the primary culture of RTCs from old kidneys while treating cells with rapamycin and chloroquine.…”

Section: Discussionmentioning

confidence: 99%

“…Since available methods for the treatment of AKI are scarce and applied strategies are mostly symptomatic and mostly limited by the use of hemodialysis, the development of alternative specific approaches for therapy is needed [ 23 ]. However, the effectiveness of these elaborated approaches should be tested both in young and old animals, since approaches that have been shown to be efficient in young organisms, not always retained their protective effects in the elderly [ 24 ]. In particular, ischemic pre- and postconditioning, demonstrating a significant reduction of the severity of ischemic injury in the renal tissue of young animals, had no effect in old animals [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Age-Dependent Loss of Dietary Restriction Protective Effects in Acute Kidney Injury

Andrianova

Jankauskas

Zorova

et al. 2018

Cells

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Dietary restriction (DR) is one of the most efficient approaches ameliorating the severity of different pathological conditions including aging. We investigated the protective potential of short-term DR in the model of acute kidney injury (AKI) in young and old rats. In kidney tissue, the levels of autophagy and mitophagy were examined, and proliferative properties of renal cells obtained from rats of different age were compared. DR afforded a significant nephroprotection to ischemic kidneys of young rats. However, in old rats, DR did not provide such beneficial effect. On the assessment of the autophagy marker, the LC3 II/LC3 I ratio, and after staining the tissue with LysoTracker Green, we concluded that in old rats activity of the autophagic-lysosomal system decreased. Mitophagy, as assessed by the levels of PINK-1, was also deteriorated in old animals. Renal cells from old rats showed impaired proliferative capacity, a worse rate of recovery after ischemic injury, increased levels of oxidative stress, accumulation of lipofuscin granules and lower mitochondria membrane potential. The results suggest that the loss of DR benefits in old animals could be due to deterioration in the autophagy/mitophagy flux.

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Aged kidney: can we protect it? Autophagy, mitochondria and mechanisms of ischemic preconditioning

Abstract: AKI: acute kidney injury; I/R: ischemia/reperfusion; CR: caloric restriction; ROS: reactive oxygen species; RC: respiratory chain.

Cited by 22 publications

References 165 publications

The role of PAK1 in the sensitivity of kidney epithelial cells to ischemia-like conditions

The role of PAK1 in the sensitivity of kidney epithelial cells to ischemia-like conditions

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Mechanisms of Age-Dependent Loss of Dietary Restriction Protective Effects in Acute Kidney Injury

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