Klotho Protein Protects against Endothelial Dysfunction

Saito, Yuichiro; Yamagishi, Takahiro; Nakamura, Toshio; Ohyama, Yoshio; Aizawa, Hiroki; Suga, Tatsuo; Matsumura, Yutaka; Masuda, Hiroaki; Kurabayashi, Masahiko; Kuro‐o, Makoto; Nabeshima, Yo‐ichi; Nagai, Ryozo

doi:10.1006/bbrc.1998.8943

Cited by 262 publications

(217 citation statements)

References 19 publications

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“…34 FGF-23 and the associated co-receptor Klotho impinge on the same system. Indeed, Klotho knockout mice 35,36 (i.e., animal models characterized by high plasma levels of FGF-23 37 ) do not express NO synthase in the vascular system and exhibit almost abolished response to acetylcholine, the strongest stimulant of NO activity. 36 Our findings show that ADMA has a variable influence on renal outcomes across the spectrum of FGF-23 values because it is associated with a higher risk for CKD progression only when FGF-23 levels are in the low-normal range (i.e., when the expression of NO synthase is not suppressed by FGF-23-Klotho).…”

Section: Discussionmentioning

confidence: 99%

“…This possibility has biologic plausibility because the gene expression of NO synthase is almost entirely abolished when FGF-23 levels are elevated, such as in the Klotho knockout mice. 35,36 Therefore, in this situation minimal or no effect of ADMA on NO synthesis can be envisaged and vice versa. Thus, FGF-23 and ADMA act jointly rather than independently on NO-dependent mechanisms, impinging upon renal integrity and renal function.…”

Section: Discussionmentioning

confidence: 99%

“…Their competitive interaction can be seen as an experiment where we injected a fixed dose of ADMA at progressively increasing levels of FGF-23. Because high FGF-23-Klotho almost completely suppresses NO synthase, 35,36 ADMA at high FGF-23 levels has no effect on the risk of CKD progression, an outcome strongly influenced by the NO system. 24 The observation that in the MMKD cohort not only ADMA but also SDMA (i.e., a methylarginine that inhibits NO synthesis by reducing cellular L-arginine uptake) showed a competitive interaction with c-terminal FGF-23 adds circumstantial support to our interpretation that these interactions depend on the interference of FGF-23-Klotho with the NO system.…”

Section: Discussionmentioning

confidence: 99%

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Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

Tripepi

Kollerits

Leonardis

et al. 2015

Journal of the American Society of Nephrology

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Both fibroblast growth factor 23 (FGF-23) and asymmetric dimethylarginine (ADMA) are associated with progression of CKD. We tested the hypothesis that ADMA and FGF23 are interactive factors for CKD progression in a cohort of 758 patients with CKD in Southern Europe (mean eGFR6SD, 36613 ml/min per 1.73 m 2 ) and in a central European cohort of 173 patients with CKD (MMKD study, mean eGFR, 64639 ml/min per 1.73 m 2 ). In the first cohort, 214 patients had renal events (decrease in eGFR of .30%, dialysis, or kidney transplantation) during a 3-year follow-up. Both intact FGF-23 and ADMA predicted the incidence rate of renal events in unadjusted and adjusted analyses (P,0.001). There was a strong competitive interaction between FGF-23 and ADMA in the risk of renal events (P,0.01 in adjusted analyses); the risk associated with raised ADMA levels was highest in patients with low FGF-23 levels. These results were confirmed in the MMKD cohort, in which FGF-23 level was again an effect modifier of the relationship between plasma ADMA level and renal events (doubling of baseline serum creatinine, dialysis, or kidney transplantation) in the adjusted analyses (P,0.01). Furthermore, in the MMKD cohort there was a parallel, independent competitive interaction between symmetric dimethylarginine level and c-terminal FGF-23 level for the risk for renal events (P=0.001). These findings indicate that the association of ADMA level with the risk of CKD progression is modified by FGF-23 level and provide further evidence that dysregulation of the nitric oxide system is involved in CKD progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

Tripepi

Kollerits

Leonardis

et al. 2015

Journal of the American Society of Nephrology

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“…The Klotho gene is only one of several known factors, e.g., NO, oxidative stress related to mitochondrial dysfunction, renin-angiotensin system, and cell-cycle proteins and length of telomeres that are relevant to the blood borne circulatory stress of aging. The NO production may be aberrant in Kl Ϫ/Ϫ mice because they exhibit impaired vasodilation (15) and angiogenesis (16) with the loss of the protective effect of the Klotho protein on the cardiovascular system (17). Remarkably, in vivo Klotho gene delivery increases endothelial-derived NO production and abrogates cardiovascular complications in a rat model with multiple atherogenic risk factors (18).…”

Section: Discussionmentioning

confidence: 99%

Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Haruna

Kashihara

Satoh

et al. 2007

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

224

212

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Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was Ϸ30% in ICGN mice, and Ϸ70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in ␤-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.aging ͉ glomerulonephritis ͉ oxidative stress ͉ tubular interstitial disease T he Klotho gene was originally identified by insertional mutagenesis, and it encodes a 130-kDa transmembrane protein that shares sequence homology with ␤-glucosidase (1). The gene is predominantly expressed in the kidney and, to a lesser extent, in the brain and reproductive and endocrine organs. Its deletion in mice (Kl Ϫ/Ϫ ) results in the development of a syndrome resembling human aging, including shortened life span, growth retardation, infertility, arteriosclerosis, skin and muscle atrophy, osteoporosis, and pulmonary emphysema (1). Conversely, overexpression of the Klotho gene extends the life span in mice (2). Although kl Ϫ/Ϫ mice do not show any overt renal abnormalities, the Klotho mRNA expression in the kidneys has been shown to be greatly reduced in patients with chronic renal failure (3). Notably, most of the features of Klotho gene-deleted mice are similar to those of the patients with chronic renal failure. In addition, Klotho gene expression has been found to be reduced in acute renal failure in ischemia-reperfusion injury murine models (4). These findings would imply that the reduction of Klotho protein may be relevant to the pathophysiology of renal failure. However, little is known concerning whether Klotho protein itself could exert an ameliorative effect on a diseased kidney to preserve its renal functions and thus could serve as a therapeutic target in various ...

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“…In klotho mutant mice, a part of the gene product does not have a transmembrane domain and could therefore be released as a soluble form . Parabiosis experiments have supported this idea (Saito et al 1998).…”

Section: Figurementioning

confidence: 90%

Klotho-deficient mice are resistant to bone loss induced by unloading due to sciatic neurectomy

Yamashita¹,

Sekiya²,

Kawaguchi³

et al. 2001

Journal of Endocrinology

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Unloading induces bone loss as seen in experimental animals as well as in space flight or in bed-ridden conditions; however, the mechanisms involved in this phenomenon are not fully understood. Klotho mutant mice exhibit osteopetrosis in the metaphyseal regions indicating that the klotho gene product is involved in the regulation of bone metabolism. To examine whether the klotho gene product is involved in the unloading-induced bone loss, the response of the osteopetrotic cancellous bones in these mice was investigated. Sciatic nerve resection was conducted using klotho mutant (kl/kl) and control heterozygous mice (+/kl) and its effect on bone was examined by micro-computed tomography ( CT). As reported previously for wild-type mice (+/+), about 30% bone loss was induced in heterozygous mice (+/kl) by unloading due to neurectomy within 30 days of the surgery. By contrast, kl/kl mice were resistant against bone loss induced by unloading after neurectomy. Unloading due to neurectomy also induced a small but significant bone loss in the cortical bone of the mid-shaft of the femur in the heterozygous mice; no reduction in the cortical bone was observed in kl/kl mice. These results indicate that klotho mutant mice are resistant against bone loss induced by unloading due to neurectomy in both cortical and trabecular bone and indicate that klotho is one of the molecules involved in the loss of bone by unloading.

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Klotho Protein Protects against Endothelial Dysfunction

Cited by 262 publications

References 19 publications

Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Klotho-deficient mice are resistant to bone loss induced by unloading due to sciatic neurectomy

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