Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of
            <i>klotho</i>
            Gene Expression

Takeshita, Kyosuke; Fujimori, Toshihiko; Kurotaki, Yoko; Honjo, Haruo; Tsujikawa, Hiroshi; Yasui, Kohichiroh; Lee, Jong-Kook; Kamiya, Kaichiro; Kitaichi, Kiyoyuki; Yamamoto, Kōji; Ito, Masafumi; Kondo, Takahisa; Iino, Shigeo; Inden, Yasuya; Hirai, Makoto; Murohara, Toyoaki; Kodama, Itsuo; Nabeshima, Yo‐ichi

doi:10.1161/01.cir.0000124224.48962.32

Cited by 199 publications

(154 citation statements)

References 18 publications

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“…1,12,21 aKlotho protein expression is detected in renal tubules, 21,46 choroid plexus, 46 islet cells in pancreas, 47 and the parathyroid gland. 11,48,49 However, the high expression in the kidney does not necessarily indicate that circulating aKlotho is of renal origin.…”

Section: Resultsmentioning

confidence: 99%

“…Both proximal convoluted tubules and distal convoluted tubules express aKlotho protein and transcripts, 21 but we do not know whether both segments release aKlotho into the circulation. It is unclear whether other organs contribute to circulating soluble aKlotho in physiologic 11,12,45,48,64 or pathologic states. 65 Lindberg and colleagues generated a conditional partial aKlotho deletion in renal tubules 45 with a similar phenotype as global aKlotho deletion.…”

Section: Discussionmentioning

confidence: 99%

“…4,[7][8][9] aKlotho is a type-I single-pass transmembrane protein with a long extracellular region harboring b-glucosidase-like motifs called Kl domains. 1,5,6,10 aKlotho expression is restricted to a few organs including the kidney, 1 parathyroid glands, 11 and sinoatrial node 12 where it forms tetrameric complexes with FGFR1c, 3c, or 4 (2Klotho:2FGFR), and serves as the high-affinity receptor for circulating FGF23 to regulate mineral metabolism. 4,[13][14][15] bKlotho is expressed in the liver and fat and forms complexes with FGFR1c or 4 to support FGF15/19 and FGF21 signaling.…”

mentioning

confidence: 99%

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Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

228

254

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ABSTRACTaKlotho is a multifunctional protein highly expressed in the kidney. Soluble aKlotho is released through cleavage of the extracellular domain from membrane aKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating aKlotho production and handling is incompletely understood, however. Here, we found higher aKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum aKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of aKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous aKlotho in anephric rats was four-to five-fold longer than that in normal rats, and exogenously injected labeled recombinant aKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that aKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in aKlotho homeostasis, producing and releasing aKlotho into the circulation and clearing aKlotho from the blood into the urinary lumen.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

228

254

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“…Although the Klotho gene encodes a type I membrane protein, its effects seem to be wide spread and systemic rather than cell-autonomous where it is primarily expressed (14) and thus could act as a circulating factor like another endogenously produced hormone by the kidney, erythropoietin. In this regard, the literature data indicate that the N-terminal extracellular domain of the Klotho protein is shed and secreted into the blood and potentially functions as a humoral factor that modulates the intracellular insulin/insulin-like growth factor 1-signaling cascade, which partly may contribute to the mechanism of extended life span (2).…”

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.

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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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“…Because of the universal mortality of kl/kl (silencing of both alleles) mice during stress, 32 we assessed cardiac function only in heterozygous Klotho-deficient (kl/+) mice by magnetic resonance imaging (MRI). At 12 weeks, the body weights were similar in kl/+ (23.862.2 g; n=11), wild-type (WT) (24.161.9 g; n=12), and transgenic Klotho-overexpressing mice (Tg-Kl; 22.361.9 g; n=12), and kl/+ mice had lower ejection fraction (Supplemental Movie 1), stroke volume, and cardiac output ( Figure 1, A-C) and thicker left ventricular wall compared with WTand Tg-Kl mice (Figure 1, D and E).…”

Section: Cardiac Dysfunction Hypertrophy and Fibrosis In Klotho-defmentioning

confidence: 99%

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Hu¹,

Shi²,

Cho³

et al. 2015

Journal of the American Society of Nephrology

235

300

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Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiencygenetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-b1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-b1-or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging.

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Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression

Cited by 199 publications

References 18 publications

Renal Production, Uptake, and Handling of Circulating αKlotho

Renal Production, Uptake, and Handling of Circulating αKlotho

Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

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