Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

Lim, Sun Woo; Shin, Yoo Jin; Luo, Kun; Quan, Yi; Ko, Eun Jeong; Chung, Byung Ha; Yang, Chul Woo

doi:10.1096/fj.201800751r

Cited by 34 publications

(32 citation statements)

References 33 publications

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“…Furthermore, urolithin A treatment enhanced TFEB expression, thus, promoting autophagy and ameliorating renal IR injury [183]. In immunosuppressant tacrolimus (Tac)-induced renal injury, impaired autophagy was found to be in tubules, which exhibited FoxO3-mediated autophagy associated with a reduction of TFEB [184]. In addition, Klotho protected Tac-induced renal injury by restoring lysosomal function and improving autophagy by inducing nuclear translocation of TFEB through inhibiting phosphorylation of glycogen synthase kinase 3β (GSK3β) [184].…”

Section: Tfeb-mediated Autophagy Induction and Renal Injurymentioning

confidence: 99%

“…In immunosuppressant tacrolimus (Tac)-induced renal injury, impaired autophagy was found to be in tubules, which exhibited FoxO3-mediated autophagy associated with a reduction of TFEB [184]. In addition, Klotho protected Tac-induced renal injury by restoring lysosomal function and improving autophagy by inducing nuclear translocation of TFEB through inhibiting phosphorylation of glycogen synthase kinase 3β (GSK3β) [184]. A recent study has demonstrated TFEB-mediated autophagic clearance of proteolipid aggregates in a mouse model of Batten disease in mTORC1-independent and Akt-dependent manners [185].…”

Section: Tfeb-mediated Autophagy Induction and Renal Injurymentioning

confidence: 99%

“…Renal IR injury Urolithin-A ↑ autophagy by enhanced TFEB expression [183] Tacrolimus-induced renal injury Klotho ↑ autophagy by enhanced nuclear translocation of TFEB [184] Lipopolysaccharide (LPS)-induced podocyte injury…”

Section: Model/ Kidney Disease Agent/drug Effect On Autophagy Referencementioning

confidence: 99%

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Autophagy Function and Regulation in Kidney Disease

et al. 2020

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Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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Section: Tfeb-mediated Autophagy Induction and Renal Injurymentioning

confidence: 99%

Section: Tfeb-mediated Autophagy Induction and Renal Injurymentioning

confidence: 99%

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Autophagy Function and Regulation in Kidney Disease

et al. 2020

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“…Additionally, our previous study found that systemic administration of α-klotho had a pro-lipolytic effect on liver and the white adipose tissue (Rao et al, 2019). Furthermore, α-klotho has been demonstrated to have a protective effect on the heart and kidneys (Guo et al, 2018;Lim et al, 2018). Generally, there are two forms of αklotho, a full-length (130 kDa) and a shorter form (65 kDa) (Xu and Sun, 2015).…”

Section: Introductionmentioning

confidence: 99%

α-Klotho Expression in Mouse Tissues Following Acute Exhaustive Exercise

Rao

Zheng

et al. 2019

Front. Physiol.

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α-Klotho, a multifunctional protein, has been demonstrated to protect tissues from injury via anti-oxidation and anti-inflammatory effects. The expression of α-klotho is regulated by several physiological and pathological factors, including acute inflammatory stress, oxidative stress, hypertension, and chronic renal failure. Exhaustive exercise has been reported to result in tissue damage, which is induced by inflammation, oxidative stress, and energy metabolism disturbance. However, little is known about the effects of exhaustive exercise on the expression of α-klotho in various tissues. To determine the effects, the treadmill exhaustion test in mice was performed and the mice were sacrificed at different time points following exhaustive exercise. Our results confirmed that the full-length (130 kDa) and shorter-form (65 kDa) α-klotho were primarily expressed in the kidneys. Moreover, we found that, except for the kidneys and brain, other tissues primarily expressed the shorter-form α-klotho, including liver, which was in contrast to previous reports. Furthermore, the shorter-form α-klotho was decreased immediately following the acute exhaustive exercise and was then restored to the pre-exercise level or even higher levels in the next few days. Our results indicate that α-klotho may play a key role in the body exhaustion and recovery following exhaustive exercise.

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“…It has been proved that Sirt1 has been regulating autophagy through the deacetylation of Atg5, Atg7, and Atg8 [224]. Autophagy extended the lifespan of mice knock-out Klotho [225], and Klotho attenuated renal lesions by regulating the autophagy clearance [226]. Based on these studies, we identified a key link between antiaging proteins like Sirt1, Klotho in DN, but further studies are still necessary to illustrate how the antiaging proteins regulate the autophagy and the exact sites for autophagy modulation.…”

Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Accelerated Kidney Aging in Diabetes Mellitus

Guo

Zheng

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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With aging, the kidney undergoes inexorable and progressive changes in structural and functional performance. These aging-related alterations are more obvious and serious in diabetes mellitus (DM). Renal accelerated aging under DM conditions is associated with multiple stresses such as accumulation of advanced glycation end products (AGEs), hypertension, oxidative stress, and inflammation. The main hallmarks of cellular senescence in diabetic kidneys include cyclin-dependent kinase inhibitors, telomere shortening, and diabetic nephropathy-associated secretory phenotype. Lysosome-dependent autophagy and antiaging proteins Klotho and Sirt1 play a fundamental role in the accelerated aging of kidneys in DM, among which the autophagy-lysosome system is the convergent mechanism of the multiple antiaging pathways involved in renal aging under DM conditions. Metformin and the inhibitor of sodium–glucose cotransporter 2 are recommended due to their antiaging effects independent of antihyperglycemia, besides angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Additionally, diet intervention including low protein and low AGEs with antioxidants are suggested for patients with diabetic nephropathy (DN). However, their long-term benefits still need further study. Exploring the interactive relationships among antiaging protein Klotho, Sirt1, and autophagy-lysosome system may provide insight into better satisfying the urgent medical needs of elderly patients with aging-related DN.

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Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

Cited by 34 publications

References 33 publications

Autophagy Function and Regulation in Kidney Disease

Autophagy Function and Regulation in Kidney Disease

α-Klotho Expression in Mouse Tissues Following Acute Exhaustive Exercise

Accelerated Kidney Aging in Diabetes Mellitus

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