Current understanding of klotho

Wang, Yuhong; Sun, Zhongjie

doi:10.1016/j.arr.2008.10.002

Cited by 268 publications

(256 citation statements)

References 97 publications

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“…31 Renal klotho expression was found to decrease in spontaneously hypertensive rats, 5/6 nephrectomized rats, noninsulin-dependent diabetes mellitus rats and in ischemia-reperfusion injury models. 32 In humans, klotho expression also decreases in CKD patients, 33 and also has protective renal effects by protecting cells/ tissues from oxidative stress and apoptosis. 29 In our study, we demonstrated that direct renin inhibition significantly increased klotho expression in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

et al. 2011

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Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, Po0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, Po0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

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Section: Discussionmentioning

confidence: 99%

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

et al. 2011

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“…Klotho homozygous (−/−) mice demonstrate early and extensive aging phenotypes and die before the age of 8 weeks (body weight = 8 g) (Kuro‐o et al ., 1997). They also develop severe hyperphosphatemia and nonselective soft tissue calcification (Wang & Sun, 2009; Xu & Sun, 2015). For these reasons, Klotho homozygous mice were not used in this study.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2

2016

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SummaryFibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti‐aging Klotho gene (KL) promotes high‐fat‐diet‐induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho‐deficient (KL +/−) mice and WT littermates were fed with a high‐fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKα activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL +/− mice than of WT mice, indicating that Klotho deficiency promotes HFD‐induced aortic valve fibrosis (AVF). AMPKα activity (pAMPKα) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL +/− mice fed with a HFD. Treatment with AICAR markedly attenuated HFD‐induced AVF in KL +/− mice. AICAR not only abolished the downregulation of pAMPKα but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL +/− mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho‐deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKα by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol‐induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD‐induced fibrosis in aortic valves, likely through the AMPKα–RUNX2 pathway.

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“…As an aging-suppressor gene, KLOTHO encodes a transmembrane protein that is predominantly secreted by the choroid plexus of the brain and kidney (Kuro-o 2009;Kuro-o et al 1997;Wang and Sun 2009). The potential involvement of the SNP G-395A in KLOTHO gene function remains speculative.…”

Section: Discussionmentioning

confidence: 99%

“…Aging, which is defined as the age-related decline in physiological functions (Wang and Sun 2009), is inevitable in multicellular organisms. Genetic influences are critical factors in the aging process.…”

Section: Introductionmentioning

confidence: 99%

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G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old

Qin

Ding

Gao

et al. 2016

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This study aimed to examine the possible association between G-395A polymorphism in the promoter region of the KLOTHO gene and cognitive impairment among Chinese nonagenarians and centenarians. This study is a secondary analysis of the Project of Longevity and Aging in Dujiangyan (PLAD) study. Community-dwelling Chinese people aged 90 years or older were included. G-395A (rs1207568) genotyping in the promoter region of the KLOTHO gene was performed using the TaqMan allelic discrimination assay. Cognitive function was assessed with the mini-mental status examination (MMSE). A total of 706 participants (68.0 % female; mean age 93.5 ± 3.6 years) were included. The KLOTHO G-395A polymorphism genotype frequencies for the whole sample were 2.0 % AA, 30.3 % GA, and 67.7 % GG. The GG genotype frequencies for the cognitive impairment and control groups were 70.2 and 62.7 %, respectively. Cognitive impairment prevalence was significantly lower in the GA+AA group than in the GG genotype group (61.4 vs. 69.0 %, p = 0.044). GA+AA genotype subjects had a significantly lower risk of cognitive impairment (odds ratio 0.66; 95 % confidence interval 0.44 to 0.98) than GG genotype individuals after adjusting for age, gender, and other relevant risk factors. KLOTHO G-395A polymorphism associates with reduced cognitive impairment in a sample of Chinese nonagenarians and centenarians.

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Current understanding of klotho

Cited by 268 publications

References 97 publications

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2

G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old

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