Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury

Liu, Shuya; Hartleben, Björn; Kretz, Oliver; Wiech, Thorsten; Igarashi, Peter; Mizushima, Noboru; Walz, Gerd; Huber, Tobias B.

doi:10.4161/auto.19419

Cited by 222 publications

(248 citation statements)

References 37 publications

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“…Autophagy is readily induced by renal ischemia-reperfusion 2,3 and cisplatin damage to the kidneys. 2,36 Reduced autophagic activity worsens acute kidney injury, 2,4,37 suggesting that stress-inducible autophagy is renoprotective. To date, dysre- gulation of tubular autophagy in kidney under diabetic conditions has not been reported.…”

Section: Discussionmentioning

confidence: 99%

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Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux

Huang

Lin

Cheng

et al. 2014

Laboratory Investigation

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Thioredoxin-interacting protein (TXNIP) expression is ubiquitous and is induced by a variety of cellular stresses, including high intracellular glucose. TXNIP is associated with activation of oxidative stress and tubulointerstitial fibrosis in diabetic nephropathy. Autophagy is a major pathway that delivers damaged proteins and organelles to lysosomes to maintain cellular homeostasis. This study aimed to investigate the dysregulation of autophagy and the regulation of TXNIP on autophagy in renal proximal tubular cells (PTCs) under diabetic conditions. The formation of autophagosomes was measured using transmission electron microscopy, and LC3-II, and the effectiveness of autophagic clearance was determined by p62 expression in diabetic kidney and in human PTCs exposed to high glucose (HG). The results collectively demonstrated increased expression of TXNIP, LC3/LC3-II and p62 in renal tubular cells of mice with diabetic nephropathy and in cultured human PTCs exposed to HG (30 mM/l) for 48 h compared with control. The formation of autophagic vacuoles was increased in HG-induced cells. Furthermore, silencing of TXNIP by siRNA transfection reduced autophagic vacuoles and the expression of LC3-II and p62 in human PTCs exposed to HG compared with control and partially reversed the accumulation of LC3-II and p62 induced by bafilomycin A 1 (50 nM/l), a pharmacological inhibitor of autophagy which blocks the fusion of autophagosomes with lysosomes and impairs the degradation of LC3-II and p62. Collectively, these results suggest that hyperglycemia leads to dysfunction of autophagy in renal tubular cells and decreases autophagic clearance. HG-induced overexpression of TXNIP may contribute to the dysfunction of tubular autophagy in diabetes.

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Section: Discussionmentioning

confidence: 99%

“…Renal tubular cell autophagy is known to be renoprotective in acute kidney injury induced by ischemia-reperfusion injury. [2][3][4] Constitutive and induced autophagy is a major protective mechanism against podocyte aging and glomerular injury. 5 Moreover, autophagy dysregulation is associated with intracellular stresses that are inherent in diabetes mellitus.…”

mentioning

confidence: 99%

Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux

Huang

Lin

Cheng

et al. 2014

Laboratory Investigation

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“…Defective autophagy can contribute to the age-dependent accumulation of damaged proteins and organelles leading to altered cellular homeostasis and loss of function. [1][2][3][4][5] The metabolic roles of autophagy can be classified into two types, basal and induced. In nutrient-rich conditions, autophagy is suppressed but still occurs at low levels (basal autophagy); however, when cells are subjected to stress (starvation, injury, hypoxia), autophagy is activated immediately (induced autophagy).…”

mentioning

confidence: 99%

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

et al. 2015

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Damage and loss of the postmitotic photoreceptors is a leading cause of blindness in many diseases of the eye. Although the mechanisms of photoreceptor death have been extensively studied, few studies have addressed mechanisms that help sustain these non-replicating neurons for the life of an organism. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomal pathway for degradation. It is not only a major pathway activated in response to cellular stress, but is also important for cytoplasmic turnover and to supply the structural and energy needs of cells. We examined the importance of autophagy in photoreceptors by deleting the essential autophagy gene Atg5 specifically in rods. Loss of autophagy led to progressive degeneration of rod photoreceptors beginning at 8 weeks of age such that by 44 weeks few rods remained. Cone photoreceptor numbers were only slightly diminished following rod degeneration but their function was significantly decreased. Rod cell death was apoptotic but was not dependent on daily light exposure or accelerated by intense light. Although the light-regulated translocation of the phototransduction proteins arrestin and transducin were unaffected in rods lacking autophagy, Atg5-deficient rods accumulated transducin-α as they degenerated suggesting autophagy might regulate the level of this protein.This was confirmed when the light-induced decrease in transducin was abolished in Atg5-deficient rods and the inhibition of autophagy in retinal explants cultures prevented its degradation. These results demonstrate that basal autophagy is essential to the long-term health of rod photoreceptors and a critical process for maintaining optimal levels of the phototransduction protein transducin-α. As the lack of autophagy is associated with retinal degeneration and altered phototransduction protein degradation in the absence of harmful gene products, this process may be a viable therapeutic target where rod cell loss is the primary pathologic event. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomes for degradation. Defective autophagy can contribute to the age-dependent accumulation of damaged proteins and organelles leading to altered cellular homeostasis and loss of function. [1][2][3][4][5] The metabolic roles of autophagy can be classified into two types, basal and induced. In nutrient-rich conditions, autophagy is suppressed but still occurs at low levels (basal autophagy); however, when cells are subjected to stress (starvation, injury, hypoxia), autophagy is activated immediately (induced autophagy). 6 Induced autophagy maintains the amino acid pool inside cells to adapt to starvation while constitutive autophagy has been shown to function as a cell-repair mechanism that is important for long-lived postmitotic cells. 7-11 Defects in autophagy have been associated with neurodegenerative diseases, 12-15 diabetes, 16,17 lysosomal storage disease 18 and the loss of vision. 19 In addition to macroautophagy, m...

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“…Transplantation/ischemia -Autophagy stimulation during renal IR is a protective mechanism to maintain energy production during the hypoxic starvation period of ischemia and/or counteract oxidative damaged proteins and organelles during reperfusion [55][56][57][58] -Autophagy contributes to renal IR damage [59][60][61][62][63][64] -In proximal tubule-specific ATG5-and ATG7-knockout mice: autophagy is protective during renal IR [55-57] -Autophagy is considered protective when ischemic duration is short (20-40 min), but detrimental when ischemic stress is severe (40-60 min) [70] Conclusion: Opposite observations because of use of non-specific compounds, different experimental models (gender, age, sex) and varying degrees of IR stress. …”

Section: Diabetic Nephropathy (Dn)mentioning

confidence: 99%

“…However, the exact outcome of autophagy stimulation in renal IR injury is still a matter of debate. Although it may seem logical to reinforce autophagy during renal IR as a protective mechanism to maintain energy production during the hypoxic starvation period of ischemia and/or counteract oxidative damaged proteins and organelles during reperfusion [55][56][57][58], several reports have made opposite observations in which autophagy contributed to renal IR damage [59][60][61][62][63][64]. Possible reasons for these conflicting findings are likely multiple.…”

Section: Transplantation/ischemiamentioning

confidence: 99%

Autophagy in renal diseases

et al. 2015

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Autophagy is the cell biology process in which cytoplasmic components are degraded in lysosomes to maintain cellular homeostasis and energy production. In the healthy kidney, autophagy plays an important role in the homeostasis and viability of renal cells such as podocytes and tubular epithelial cells and of immune cells. Recently, evidence is mounting that (dys)regulation of autophagy is implicated in the pathogenesis of various renal diseases, and might be an attractive target for new renoprotective therapies. In this review, we provide an overview of the role of autophagy in kidney physiology and kidney diseases.

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Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury

Abstract: These authors contributed equally to this work.

Cited by 222 publications

References 37 publications

Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux

Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

Autophagy in renal diseases

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