The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

Shi, Mingjun; Maique, Jenny; Shaffer, Joy; Davidson, Taylor L; Sebti, Salwa; Fernández, Álvaro F.; Zou, Zhongju; Yan, Shirley; Moe, Orson W.; Hu, Ming

doi:10.1096/fj.201902127r

Cited by 17 publications

(37 citation statements)

References 88 publications

(222 reference statements)

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“…Accumulation of misfolded proteins further contributed to cell senescence and potentiated renal fibrosis 158 . α-Klotho, a type 1 transmembrane protein, is originally identified as an aging suppressor and can be released into circulation and exert multiple effects on target organs.α-Klotho expression deficiency was shown to be responsible for endothelial dysfunction, microangiopathy and fibrosis 168 . Similarly, a recent article showed that αKlotho activation attenuated renal fibrosis, protected renal cells from oxidative stress and suppressed the progression of AKI to CKD through the upregulation of autophagy flux, which was reversed in α-Klotho deficiency mouse model 169 .…”

Section: Kidney Fibrosis and Autophagymentioning

confidence: 99%

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Liu¹,

Wu²,

Li³

2020

Theranostics

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Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.

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Section: Kidney Fibrosis and Autophagymentioning

confidence: 99%

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Liu¹,

Wu²,

Li³

2020

Theranostics

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“…Four μm sections of paraffin-embedded kidney or cryosections were used for immunohistochemistry following protocols previously published ( Li et al., 2020 ; Shi et al., 2020 ). For non-nuclear protein staining, paraffin-embedded kidney sections were de-waxed and rehydrated, then heated in a microwave in 10 mM citrate buffer (pH 6.0) for 30 min (20 min in boiling conditions) to retrieve antigens.…”

Section: Methodsmentioning

confidence: 99%

“…Aging is an inevitable multi-organ deterioration initiated and accelerated by multiple factors. We have shown that Klotho deficiency and excess phosphate (Pi) have detrimental effects on aging ( Fernandez et al., 2018 ; Shi et al., 2020 ). Compelling observational and animal studies showed that phosphotoxicity is associated with reduced longevity in several species ( Kuro-O, 2010 ; Shi et al., 2020 ) and causes severely abnormal metabolism and ill effects on bone, kidney, cardiovasculature, and other organs in chronic kidney disease (CKD) ( Kestenbaum et al., 2005 ; Tonelli et al., 2005 ; John et al., 2011 ; Calvo et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…We have shown that Klotho deficiency and excess phosphate (Pi) have detrimental effects on aging ( Fernandez et al., 2018 ; Shi et al., 2020 ). Compelling observational and animal studies showed that phosphotoxicity is associated with reduced longevity in several species ( Kuro-O, 2010 ; Shi et al., 2020 ) and causes severely abnormal metabolism and ill effects on bone, kidney, cardiovasculature, and other organs in chronic kidney disease (CKD) ( Kestenbaum et al., 2005 ; Tonelli et al., 2005 ; John et al., 2011 ; Calvo et al., 2019 ). However, the molecular mechanisms by which Pi mediates acceleration of aging, and initation and excerbation of cardiovascular disease in CKD are complex, multifactorial, and not fully understood ( Ohnishi and Razzaque, 2010 ; Osuka and Razzaque, 2012 ; Hu et al., 2015 ; Ritter and Slatopolsky, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Kidney fibrosis is one of the hallmarks of the aged kidney and of CKD, and also a deleterious driver for CKD progression ( Cruz et al., 2000 ; Torres and Leof, 2011 ; Yang and Fogo, 2014 ; Humphreys, 2018 ). We previously showed that high Pi decreases circulating and kidney Klotho and induces kidney fibrosis, while low Klotho increases plasma Pi and synergistically exacerbates kidney fibrosis induced by high Pi diet ( Hu et al., 2015 ; Shi et al., 2020 ). However, whether kidney fibrosis associated with Klotho deficiency is mediated through modulation of senescence remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

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High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis

et al. 2020

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Cellular senescence is an irreversible cell growth arrest and is associated with aging and age-related diseases. High plasma phosphate (Pi) and deficiency of Klotho contribute to aging and kidney fibrosis, a pathological feature in the aging kidney and chronic kidney disease. This study examined the interactive role of Pi and Klotho in kidney senescence and fibrosis. Homozygous Klotho hypomorphic mice had high plasma Pi, undetectable Klotho in plasma and kidney, high senescence with massive collagen accumulation in kidney tubules, and fibrin deposits in peritubular capillaries. To examine the Pi effect on kidney senescence, a high (2%) Pi diet was given to wild-type mice. One week of high dietary Pi mildly increased plasma Pi, and upregulated kidney p16/p21 expression, but did not significantly decrease Klotho. Two weeks of high Pi intake led to increase in plasminogen activator inhibitor (PAI)-1, and decrease in kidney Klotho, but still without detectable increase in kidney fibrosis. More prolonged dietary Pi for 12 weeks exacerbated kidney senescence and fibrosis; more so in heterozygous Klotho hypomorphic mice compared to wild-type mice, and in mice with chronic kidney disease (CKD) on high Pi diet compared to CKD mice fed a normal Pi diet. In cultured kidney tubular cells, high Pi directly induced cellular senescence, injury and epithelialmesenchymal transition, and enhanced H 2 O 2-induced cellular senescence and injury, which were abrogated by Klotho. Fucoidan, a bioactive molecule with multiple biologic functions including senescence inhibition, blunted Pi-induced cellular senescence, oxidation, injury, epithelial-mesenchymal transition, and senescence-associated secretary phenotype. In conclusion, high Pi activates senescence through distinct but interconnected mechanisms: upregulating p16/p21 (early), and elevating plasminogen activator inhibitor-1 and downregulating Klotho (late). Klotho may be a promising agent to attenuate senescence and ameliorate age-associated, and Pi-induced kidney degeneration such as kidney fibrosis.

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Phosphate and Cellular Senescence

Moe

2022

Advances in Experimental Medicine and Biology

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The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

Cited by 17 publications

References 88 publications

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis

Phosphate and Cellular Senescence

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