Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease

Franco, Marcella Liciani; Beyerstedt, Stephany; Rangel, Érika B.

doi:10.3390/pharmaceutics14010011

Cited by 13 publications

(7 citation statements)

References 340 publications

(501 reference statements)

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“…Given that CKD is related to the prevalence of CHF, the repletion of Klotho production may give renal protection and, as a result, may help to decrease the prevalence of CHF ( 57 ). Dysregulation of Klotho axis leads to higher cardiovascular risk resulting in increased cardiovascular morbidity and mortality rates of CKD patients ( 58 ). In our study, renal function was found to significantly mediate the association between Klotho and CHF, which may signify Klotho playing important roles in the pathogenesis of CHF.…”

Section: Discussionmentioning

confidence: 99%

Renal Function Mediates the Association Between Klotho and Congestive Heart Failure Among Middle-Aged and Older Individuals

Zhu

Yin

et al. 2022

Front. Cardiovasc. Med.

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ObjectiveUsing a newly released National Health and Nutrition Examination Survey (NHANES) data of serum Klotho, this study aimed to explore the relationship between Klotho and specific cardiovascular diseases (CVD), as well as the mediation effect of renal function, among middle-aged and older individuals within the general population.MethodsThis nationally representative cross-sectional study analyzed data from the 2007–2016 NHANES. A total of 13,765 participants, who aged 40 years or older, from the general population were examined. Klotho were divided into four groups based on median and interquartile range. The associations among Klotho (exposure), congestive heart failure (CHF; outcome), and renal function markers [estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid (UA), and urine albumin-to-creatinine ratio (UACR); mediators] were investigated using mediation analysis.ResultsIn comparison to the lowest quartile, Klotho in the highest quartile was independently associated with the prevalence of CHF (OR 0.59; 95% CI 0.46–0.77, p for trend = 0.001), but not with other individual CVDs. Klotho had a significant direct effect on the prevalence of CHF (all p < 0.001), while eGFR, BUN, UA, and UACR partly mediated the indirect effect of Klotho on the prevalence of CHF (all p < 0.05), explaining 19.51, 6.98, 13.93, and 0.71% of the association between Klotho and CHF, respectively. Additionally, restricted cubic spline regression demonstrated a linear association and negative correlation between Klotho level and CHF.ConclusionThese findings suggest that Klotho is closely linked to CHF and renal function may be a key mediator of this association.

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Section: Discussionmentioning

confidence: 99%

Renal Function Mediates the Association Between Klotho and Congestive Heart Failure Among Middle-Aged and Older Individuals

Zhu

Yin

et al. 2022

Front. Cardiovasc. Med.

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“…Specific examples of the administration of recombinant s-Klotho or peptides were discussed before. Gene therapy has been performed with viral vectors or plasmids, and cell therapy also appears feasible ( Franco et al, 2021 ). In some cases, such as recombinant protein and gene therapies, the feasibility, potential adverse effects, accessibility, and high cost are likely to be limiting factors.…”

Section: Approaches To Klotho-based Therapymentioning

confidence: 99%

“…Recombinant Klotho protein or peptides: Ali et al, 2020 ; Chen TH, et al, 2013 ; Doi et al, 2011 ; Gupta et al, 2022 ; Hu et al, 2017 ; Leon et al, 2017 ; Maltese et al, 2017 ; Mencke et al, 2017 ; Myung et al, 2022 ; Oh et al, 2018 ; Prud’homme et al, 2020 ; Rao Z, et al, 2019 ; Takenaka et al, 2018 , 2019 , 2020 ; Yang et al, 2015 ; Yuan et al, 2022 ; Zhong et al, 2020 . Gene therapy: Arbel Rubinstein et al, 2021 ; Franco et al, 2021 ; Lin & Sun, 2015a , b ; Ni et al, 2021 ; Mencke et al, 2017 ; Shin et al, 2019 ; Xiang et al, 2021 ; Zeng et al, 2019 . Traditional medicines, nutraceuticals and supplements: Dehghani et al, 2019 ; Feng and Huang, 2022 ; Hsu et al, 2014 ; Kamel et al, 2022 ; Long et al, 2018 ; Li SS, et al, 2018 ; Lim SW, et al, 2019 ; Long et al, 2018 ; Ostojic and Engeset, 2021 ; Zhang P, et al, 2016 ; Zhang XT, et al, 2020 ; Zhou et al, 2015 .…”

Section: Approaches To Klotho-based Therapymentioning

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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“…17 Klotho protein is implicated in the endocrine regulation of mineral metabolism and the regulation of multiple signalling pathways. 18 FGF23 exerts its biological functions by activating the fibroblast growth factor receptor (FGFR) in renal tissues in a Klotho-dependent manner. 19 Through binding to Klotho and triggering downstream mitogenactivated protein kinase (MAPK) signalling, FGF23 induces oxidative stress and inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

“…The Klotho gene, mainly expressed on kidney distal tubular epithelial cells, is able to generate unidirectional transmembrane proteins 17 . Klotho protein is implicated in the endocrine regulation of mineral metabolism and the regulation of multiple signalling pathways 18 . FGF23 exerts its biological functions by activating the fibroblast growth factor receptor (FGFR) in renal tissues in a Klotho‐dependent manner 19 .…”

Section: Introductionmentioning

confidence: 99%

LncRNA 152 attenuates lipopolysaccharide‐induced acute kidney injury in rats by regulating the FGF23/Klotho/MAPK axis

Lei,

Zhang,

Hou

et al. 2023

Nephrology

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AimThis study aimed to explore the effect and related mechanisms of LncRNA 152 in acute kidney injury (AKI).MethodsQRT‐PCR was used to detect the expression of LncRNA 152, FGF23 and Klotho in the serum of patients with AKI. Subsequently, Sprague Dawley (SD) rats were induced into AKI animal model by lipopolysaccharide (LPS). Then, H&E staining was performed to observe the pathological changes in the rat kidney tissues; qRT‐PCR to detect the expression of LncRNA 152, FGF23 and Klotho in the rat kidney tissues; biochemical assay and ELISA to assess the levels of renal function indexes and inflammatory factors in rat serum, as well as oxidative stress indexes in kidney tissues; and western blot to measure the protein expressions of FGF23, Klotho, p‐p38 and p38 in rat kidney tissues.ResultsLncRNA 152 was significantly down‐regulated in serum of AKI patients and kidney tissues of AKI rats. In AKI patients, LncRNA 152 was negatively correlated with FGF23 expression while positively correlated with Klotho expression. LncRNA 152 overexpression reduced the levels of blood urea nitrogen (BUN), creatinine (Cr) and cystatin C (Cys‐C) and inflammatory factors in serum of AKI rats and attenuated pathological damage and oxidative stress of kidney tissues. In addition, LncRNA 152 overexpression also decreased FGF23 expression and p‐p38/p38 ratio while up‐regulated Klotho expression in the kidney tissues of AKI rats.ConclusionLncRNA 152 attenuates oxidative stress and inflammatory responses by regulating the FGF23/Klotho axis and inhibiting the MAPK signalling pathway in rat kidney tissues, thereby ameliorating LPS‐induced AKI.

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Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease

Cited by 13 publications

References 340 publications

Renal Function Mediates the Association Between Klotho and Congestive Heart Failure Among Middle-Aged and Older Individuals

Renal Function Mediates the Association Between Klotho and Congestive Heart Failure Among Middle-Aged and Older Individuals

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

LncRNA 152 attenuates lipopolysaccharide‐induced acute kidney injury in rats by regulating the FGF23/Klotho/MAPK axis

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