Age-Dependent Responses to Renal Ischemia-Reperfusion Injury

Kusaka, Junya; Koga, Hironori; Hagiwara, Satoshi; Hasegawa, Akira; Kudo, Kazuhiro; Noguchi, Takayuki

doi:10.1016/j.jss.2010.08.034

Cited by 38 publications

(29 citation statements)

References 17 publications

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“…Recent studies demonstrated that there were more severe reperfusioninduced injuries and apoptotic tubular cells in the kidneys of aged rats after I/R injury. [21][22][23] Although the previous study showed that IPoC attenuated apoptosis after I/R injury, 3,8 we speculated that the more severe apoptosis may contribute to the lost protective effects of IPoC. Our results are compatible with these studies, which showed that renal I/R injury induced more severe apoptosis in aged rats which was proved by caspase-3 activity.…”

Section: Discussionsupporting

confidence: 89%

Aged kidneys are refractory to ischemic postconditioning in a rat model

et al. 2014

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Background: Ischemic postconditioning (IPoC) is defined as a series of intermittent interruptions of blood flow in the early phase of reperfusion that mechanically alters the hydrodynamics of reperfusion and it attenuates renal damage after ischemia/reperfusion (I/R) injury in vivo. But all of these data had been obtained in adult populations and whether this protection was maintained in aging kidneys was unknown. The objective of this study was to establish whether the efficacy of IPoC is maintained in aging kidneys. Materials and methods: The aged (24-monthold) and young (3-month-old) Wistar rats were used. Rats were subjected to 45 min of renal ischemia, both with and without treatment with IPoC. Serum urea nitrogen and creatinine levels, histological examination and apoptosis were assessed at 24 h. Oxidative stress was evaluated and apoptosis-related molecules were studied by Western blotting. Results: In young rat kidneys, IPoC significantly attenuated the renal dysfunction and cell apoptosis induced by I/R. In contrast, IPoC failed to limit renal dysfunction, possibly a consequence of increased apoptosis in aged rat kidneys. Conclusions: Our data indicated that IPoC was ineffective in aged rat kidneys. These findings may have major implications in that severe apoptosis in aged kidneys might be refractory to anti-apoptotic effect by IPoC.

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Section: Discussionsupporting

confidence: 89%

Aged kidneys are refractory to ischemic postconditioning in a rat model

et al. 2014

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“…48 Furthermore, ischemic injury in the elderly and patients with hyperlipidemia is a major risk factor for ESRD. 49,50 In this point, therapeutic effort to restore lysosomal function and autophagic flux will pave the way to improving the clinical outcome of kidney injury related to aging or HFD.…”

Section: Discussionmentioning

confidence: 99%

High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney

Yamamoto¹,

Takabatake²,

Takahashi³

et al. 2016

JASN

215

194

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Excessive fat intake contributes to the progression of metabolic diseases via cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases.

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“…In fact, the number of naïve T cells decreases and proinflammatory chemokine production increases after inflammatory stimulation in elderly populations [17,18]. Aging reportedly impairs the regenerative process of the kidneys after ischemic IR due to a reduced or impaired regenerative capacity of tubules [22], regulation to suppress fibrosis [23], telomere shortening [24] and a decrease in antioxidant function [25]. Aging also exaggerates heart injury induced by IR due to decreased antioxidant function [26] and increased myocyte apoptosis [27].…”

Section: Discussionmentioning

confidence: 99%

“…Since levels of AKI are increased after renal IR in aged, compared with young rats [25], the degree of renal failure might have been much higher in the 40-week-old rats before day 7. This might have also modulated the effect upon the heart and the non-IR kidney.…”

Section: Discussionmentioning

confidence: 99%

Ischemia/Reperfusion of Unilateral Kidney Exaggerates Aging-Induced Damage to the Heart and Contralateral Kidney

Kato¹,

Nakayama

Zhu³

et al. 2014

Nephron Exp Nephrol

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Aims: We aimed to determine the impact of aging on ischemic acute kidney injury, especially in terms of the pathological mechanisms of kidney and heart crosstalk. Method: The effects of 45 min of unilateral ischemic reperfusion (IR) of the renal artery on the contralateral kidney and heart were histologically assessed in 7- and 40-week-old SD rats after 7 days. Results: Glomerular sclerosis, interstitial fibrosis and numbers of ED1 cells were significantly increased in the contralateral kidneys of the 40-, but not the 7-week-old rats. The numbers of ED1 cells in the heart significantly and similarly increased in both groups, but reactive fibrosis after IR was significant only in the 40-week-old rats. The exaggerated profibrotic response induced by aging seemed to be closely associated with the increased number of ED1 cells in the affected area. Conclusion: Aging could play a major role in exaggerating the pathological processes of inflammation to fibrosis in remote organs including the heart and the nonischemic kidney after IR stimulation of the unilateral kidney.

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Age-Dependent Responses to Renal Ischemia-Reperfusion Injury

Cited by 38 publications

References 17 publications

Aged kidneys are refractory to ischemic postconditioning in a rat model

Aged kidneys are refractory to ischemic postconditioning in a rat model

High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney

Ischemia/Reperfusion of Unilateral Kidney Exaggerates Aging-Induced Damage to the Heart and Contralateral Kidney

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