Klotho ameliorates diabetic nephropathy by activating Nrf2 signaling pathway in podocytes

Xing, Lina; Guo, Hengjiang; Meng, Sixuan; Zhu, Bin; Huang, Jiebo; Chen, Junliang; Wang, Yunman; Wang, Li; Yao, Xingmei; Wang, Hao

doi:10.1016/j.bbrc.2020.11.061

Cited by 53 publications

(41 citation statements)

References 31 publications

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“…PPARγ can also activate the enzyme Klotho, which can attenuate HG-induced oxidative stress and decrease podocyte apoptosis in vitro and in vivo ( 50 ). The antioxidant effects of Klotho may in part be via activation of nuclear respiratory factor (NRF)-2 signaling ( 51 ). HG-induced Klotho deficiency can also lead to reduced DNA repair capacity in podocytes, which is, importantly, accompanied with mitochondrial dysfunction and cell injury ( 52 ).…”

Section: Mitochondrial Injury Underlies the Development Of Diabetic Nephropathymentioning

confidence: 99%

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

2021

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Diabetic Nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signalling pathways; and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarise what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.

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Section: Mitochondrial Injury Underlies the Development Of Diabetic Nephropathymentioning

confidence: 99%

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

2021

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“…Wang et al [ 12 ] displayed that KL overexpression weakened DN through ameliorating HG-triggered damage of glomerular endothelial cells. We and others also proved KL-conferred podocyte protection in DN [ 13 – 15 ]. Nevertheless, the molecular mechanism by which KL protects against podocyte injury in DN warrants further study.…”

Section: Introductionmentioning

confidence: 64%

“…KL deficiency has been implicated in glomerular pathophysiology [ 8 ]. A series of investigations have validated the protection potency of KL for podocytes in DN [ 12 , 13 , 41 ]. Nevertheless, whether and how KL directly protects podocytes are unknown.…”

Section: Discussionmentioning

confidence: 99%

Klotho Ameliorates Podocyte Injury through Targeting TRPC6 Channel in Diabetic Nephropathy

Yao

Guo

Sun

et al. 2022

Journal of Diabetes Research

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Podocyte damage is vital for the etiopathogenesis of diabetic nephropathy (DN). Klotho (KL), a multifunctional protein, has been demonstrated to have renoprotective effects; nevertheless, the mechanism for protective effect has not been completely elucidated. Transient receptor potential cation channel subfamily C, member 6 (TRPC6), a potential target of KL, is implicated in glomerular pathophysiology. Here, we sought to determine whether KL could protect against podocyte injury through inhibiting TRPC6 in DN. We found that high glucose (HG) triggered podocyte injury as manifested by actin cytoskeleton damage along with the downregulation of KL and Synaptopodin and the upregulation of TRPC6. KL overexpression reversed HG-induced podocytes injury, whereas cotreatment with TRPC6 activator flufenamic acid (FFA) significantly abrogated the beneficial effects conferred by KL. Moreover, KL knockdown in podocytes resulted in actin cytoskeleton impairment, decreased Synaptopodin expression, and increased TRPC6 expression. In db/db mice, KL overexpression inhibited TRPC6 expression and attenuated diabetes-induced podocyte injury, which was accompanied by decreased albuminuria and ameliorated glomerulosclerosis. Our data provided novel mechanistic insights for KL against DN and highlighted TRPC6 as a new target for KL in podocytes to prevent DN.

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“…Klotho activated Nrf2 in renal, cardiovascular and neurological preclinical disease models ( Maltese et al, 2017 ; Zhu et al, 2017 ; Xing et al, 2021 ; Xiang et al, 2022 ). Nrf2 is a transcription factor that controls responses to oxidative stress and toxins ( Dinkova-Kostova et al, 2018 ; Qu et al, 2020 ; Panda et al, 2022 ).…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

“…See also Table 1. Kidneys: Cheng et al, 2010;Kuro-o, 2010Kuro-o, , 2019Kuro-o, , 2021Maquigussa et al, 2018;Oishi et al, 2021;Prud'homme et al, 2017aPrud'homme et al, , 2020Saar-Kovrov et al, 2021;Takenaka et al, 2017;Xing et al, 2021;Zou et al, 2018. Cardiovascular: Chen K, et al, 2021Freunlich et al, 2021;Manrique et al, 2016;Myung et al, 2022;Martin-Nunez et al, 2022;Olejnik et al, 2018Olejnik et al, , 2020Tyrenkov et al, 2021;Wang F and Zheng, 2022;Yang et al, 2015.…”

Section: Summary Of References For Disease Relevancementioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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Klotho ameliorates diabetic nephropathy by activating Nrf2 signaling pathway in podocytes

Cited by 53 publications

References 31 publications

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

Klotho Ameliorates Podocyte Injury through Targeting TRPC6 Channel in Diabetic Nephropathy

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

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