Effect of systemically increasing human full-length Klotho on glucose metabolism in db/db mice

Forsberg, Elisabete; Olauson, Hannes; Larsson, Tobias E.; Catrina, Sergiu‐Bogdan

doi:10.1016/j.diabres.2016.01.006

Cited by 9 publications

(8 citation statements)

References 9 publications

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“…Klotho blunts insulin sensitivity, 16 whereas klotho gene delivery reduced blood glucose by increasing insulin secretion in 10-week-old db/db mice. 37 Finally, klotho administration did not alter kidney weight in control mice. Thus, disease-related decrements of endogenous klotho may underlie deleterious renal hypertrophy.…”

Section: Discussionmentioning

confidence: 91%

Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes

et al. 2018

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Aims: Klotho interacts with various membrane proteins, such as receptors for transforming growth factor (TGF)-β and insulin-like growth factor (IGF), to alter their function. Renal expression of klotho is diminished in diabetes. The present study examined whether exogenous klotho protein supplementation ameliorates kidney injury and renin–angiotensin system (RAS) in db/db mice. Methods: We investigated the effects of klotho supplementation on diabetic kidney injury and RAS. Recombinant human klotho protein (10 μg/kg/d) was administered to db/db mice daily. Results: Klotho protein supplementation reduced kidney weight, systolic blood pressure, albuminuria, glomerular filtration rate, and 8-epi-prostaglandin F2α excretion without affecting body weight. Although klotho supplementation did not alter glycated albumin, it reduced renal angiotensin II levels associated with reduced renal expression of angiotensinogen. Klotho supplementation improved renal expression of superoxide dismutase (SOD), and endogenous renal expression of klotho. Klotho supplementation reduced the levels of hypoxia-inducible factor, phosphorylated Akt, and phosphorylated mTOR and decreased the renal expression of TGF-β, tumour necrosis factor (TNF), and fibronectin. Conclusions: These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt-mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF-β and TNF signalling, resulting in a decline in renal fibrosis.

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Section: Discussionmentioning

confidence: 91%

Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes

et al. 2018

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“…In light of FGF21’s reported role in metabolism and fat homeostasis, we hypothesized that sustained overexpression of FGF21 could counter metabolic dysregulation resulting from a high-fat diet (HFD), which is an established model for obesity and type II diabetes in mice (28). It has also been observed that αKlotho can help regulate high blood glucose in diabetes models (29) and that TGFβ1 signaling and other inflammatory pathways also impact obesity and disease (30–32). Accordingly, we sought to investigate if a synergistic advantage could be achieved through the coexpression of αKlotho, FGF21, and sTGFβR2.…”

Section: Resultsmentioning

confidence: 99%

A single combination gene therapy treats multiple age-related diseases

Davidsohn

Pezone

Vernet

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceHuman and animal longevity is directly bound to their health span. While previous studies have provided evidence supporting this connection, therapeutic implementation of this knowledge has been limited. Traditionally, diseases are researched and treated individually, which ignores the interconnectedness of age-related conditions, necessitates multiple treatments with unrelated substances, and increases the accumulative risk of side effects. In this study, we address and overcome this deadlock by creating adeno-associated virus (AAV)-based antiaging gene therapies for simultaneous treatment of several age-related diseases. We demonstrate the modular and extensible nature of combination gene therapy by testing therapeutic AAV cocktails that confront multiple diseases in a single treatment. We observed that 1 treatment comprising 2 AAV gene therapies was efficacious against all 4 diseases.

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“…Klotho is now considered a strong biomarker and therapy for several diseases [3][4][5][6][7][8][9][10] . In addition, it presents anti-in ammatory and antioxidant properties [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Klotho, much more than an anti-aging protein, an emerging exerkine: A systematic review and meta-analysis

Corrêa

Raab

Araújo

et al. 2022

Preprint

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Background: Klotho is an anti-aging protein with several therapeutic roles in the pathophysiology of different organs, such as the skeletal muscle and kidneys. Available evidence suggests that exercise increases Klotho levels, regardless of the condition or intervention, shedding some light on this anti-aging protein as an emergent and promising exerkine. Objective: Development of a systematic review and meta-analysis in order to verify the role of different exercise training protocols on the levels of circulating soluble Klotho (S-Klotho) protein. Data sources: A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE through PubMed, EMBASE, CINAHL, CT.gov, and PEDro. Eligibility criteria: Randomized and quasi-randomized controlled trials that investigated effects of exercise training on S-Klotho levels. Results: We included 12 reports in the analysis, comprising 621 participants with age ranging from 30 to 65 years old. Klotho concentration increased significantly after chronic exercise training (minimum of 12 weeks) (Hedge’ g [95%CI] 1.3 [0.69 – 1.90]; P < 0.0001). Moreover, exercise training increases S-Klotho values regardless of the health condition of the individual or the exercise intervention, with the exception of combined aerobic + resistance training. Furthermore, protocol duration and volume seem to influence S-Klotho concentration, since the effect of the meta-analysis changes when subgrouping these variables. Conclusion: Altogether, circulating S-Klotho protein is altered after chronic exercise training and it might be considered an exerkine. However, this effect may be influenced by different training configurations, including protocol duration, volume, and intensity.

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Effect of systemically increasing human full-length Klotho on glucose metabolism in db/db mice

Cited by 9 publications

References 9 publications

Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes

Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes

A single combination gene therapy treats multiple age-related diseases

Klotho, much more than an anti-aging protein, an emerging exerkine: A systematic review and meta-analysis

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