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Author: Makoto Kuro-O (133)


Feb
2018

Profound disturbances in mineral metabolism are closely linked to the progression of chronic kidney disease. However, increasing clinical and experimental evidence indicate that alterations in phosphate homeostasis could have an even stronger impact on the heart. The aim of this review is to provide the reader with an update of how alterations in mineral metabolism are related to direct and indirect cardiotoxic effects beyond the nephrology setting.

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Jan
2018

Ageing-related receptors resolved.

Nature 2018 Jan;553(7689):409-410
Makoto Kuro-O

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Jan
2018

The klotho gene, which encodes a single-pass transmembrane protein and a secreted protein, is expressed predominantly by the distal renal tubules and is related to calcium-phosphorus metabolism, ion channel regulation, intracellular signaling pathways, and longevity. Klotho deficiency aggravates acute kidney injury and renal fibrosis. Exposure to nicotine also worsens kidney injury.

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Jan
2018

Calciprotein particles (CPP) are solid-phase calcium-phosphate bound to serum protein fetuin-A and dispersed as colloids in the blood. Recent clinical studies indicated that serum CPP levels were increased with decline of renal function and associated with inflammation and vascular calcification. However, CPP assays used in these studies measured only a part of CPP over a certain particle size and density.

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Jan
2018

Many of the >2 million animal species that inhabit Earth have developed survival mechanisms that aid in the prevention of obesity, kidney disease, starvation, dehydration and vascular ageing; however, some animals remain susceptible to these complications. Domestic and captive wild felids, for example, show susceptibility to chronic kidney disease (CKD), potentially linked to the high protein intake of these animals. By contrast, naked mole rats are a model of longevity and are protected from extreme environmental conditions through mechanisms that provide resistance to oxidative stress.

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Jan
2018

Duchenne muscular dystrophy (DMD) is a muscle wasting disease in which inflammation influences the severity of pathology. We found that the onset of muscle inflammation in the mdx mouse model of DMD coincides with large increases in expression of pro-inflammatory cytokines [tumor necrosis factor-α (TNFα); interferon gamma (IFNγ)] and dramatic reductions of the pro-myogenic protein Klotho in muscle cells and large increases of Klotho in pro-regenerative, CD206+ macrophages. Furthermore, TNFα and IFNγ treatments reduced Klotho in muscle cells and increased Klotho in macrophages.

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Aug
2017

Control of phosphate metabolism is crucial to regulate aging in mammals. Klotho is a well-known anti-aging factor that regulates phosphate metabolism: mice mutant or deficient in Klotho exhibit phenotypes resembling human aging. Here we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is required for Klotho expression under phosphate overload conditions.

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Dec
1969

Fibroblast growth factor 21 (FGF21) is an endocrine factor that regulates glucose and lipid metabolism. Circulating FGF21 predicts cardiovascular events and mortality in type 2 diabetes mellitus, including early-stage chronic kidney disease, but its impact on clinical outcomes in end-stage renal disease (ESRD) patients remains unclear. This study enrolled 90 ESRD patients receiving chronic hemodialysis who were categorized into low- and high-FGF21 groups by the median value.

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May
2017

Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldosterone, silencing and pharmacological inhibition (spironolactone, eplerenone) of the mineralocorticoid receptor (MR) ameliorated phosphate-induced osteo-/chondrogenic transformation of primary human aortic smooth muscle cells (HAoSMCs).

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Dec
1969

In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)-23. Abnormal regulation of the FGFR1-Klotho receptor complex may cause a resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)-1 in healthy and uremic rats induced by 5/6 nephrectomy.

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Apr
2017

Fibroblast growth factor 21 (FGF21), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF21's anorexigenic effect and the systemic energy state supporting it are unclear.

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May
2017

α-Klotho is highly expressed in the kidney, and its extracellular domain is cleaved and released into the circulation. Chronic kidney disease (CKD) is a state of α-Klotho deficiency, which exerts multiple negative systemic effects on numerous organs including the cardiovascular system. Since acute kidney injury (AKI) greatly escalates the risk of CKD development, we explored the effect of α-Klotho on prevention and treatment on post-AKI to CKD progression and cardiovascular disease.

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Jan
2017

Secondary hyperparathyroidism, in which parathyroid hormone (PTH) is excessively secreted in response to factors such as hyperphosphataemia, hypocalcaemia, and low 1,25-dihydroxyvitamin D (1,25(OH)D) levels, is commonly observed in patients with chronic kidney disease (CKD), and is accompanied by high levels of fibroblast growth factor 23 (FGF23). However, the effect of FGF23 on the parathyroid glands (PG) remains controversial. To bind to FGF receptors, FGF23 requires αKlotho, which is highly expressed in the PG.

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Jan
2017

Calciprotein particles (CPPs), colloidal protein-mineral nanoparticles composed of solid-phase calcium phosphate and serum protein fetuin-A found in blood, are emerging as a novel component of chronic kidney disease-mineral and bone disorder (CKD-MBD). In this study, we examined daily variations in CPPs as well as their association with mineral metabolism parameters in normal individuals and early-stage CKD patients.
Twenty subjects (10 healthy adults, 10 diabetic patients) were enrolled.

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Jul
2017

The vertebrate endoskeleton is not a mere frame for muscle attachment to facilitate locomotion, but is a massive organ integrated with many physiologic functions including mineral and energy metabolism. Mineral balance is maintained by tightly controlled ion fluxes that are external (intestine and kidney) and internal (between bone and other organs), and are regulated and coordinated by many endocrine signals between these organs. The endocrine fibroblast growth factors (FGFs) and Klotho gene families are complex systems that co-evolved with the endoskeleton.

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Mar
2017

The FGF23 and Klotho system beyond mineral metabolism.

Clin Exp Nephrol 2017 Mar 12;21(Suppl 1):64-69. Epub 2016 Nov 12.
Makoto Kuro-O
FGF23 is a bone-derived hormone that acts primarily on the kidney to induce phosphaturia and suppress synthesis of 1,25-dihydroxyvitamin D. The unique feature of FGF23 is that it requires Klotho as an obligate co-receptor. The FGF23-Klotho system has emerged as an endocrine axis indispensable for maintaining phosphate homeostasis.

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Dec
1969

In peripheral arterial disease (PAD) of the lower extremities, the presence of flow-limiting stenoses can be objectively detected by the ankle-brachial index (ABI). However, the severity of ischemic symptoms is not necessarily associated with the ABI value. Atherosclerotic plaque in lower extremity PAD induces ankle arterial stiffness and reduces ankle vascular resistance, which may decrease ankle blood flow and cause ischemic symptoms.

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Dec
1969

Fibroblast growth factor 23 (FGF23) regulates mineral homeostasis. In developed renal dysfunction, FGF23 levels increase to maintain the phosphate excretion capacity. However, in diabetic patients with early-stage renal impairment, the FGF23 elevation is not very sensitive.

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Jun
2016

Klotho was originally identified as an anti-aging gene that accelerated aging when disrupted and extended life span when overexpressed in mice. The Klotho gene encodes a single-pass transmembrane protein and is expressed in the kidney and parathyroid gland. Klotho protein functions as an obligate subunit of the receptor for fibroblast growth factor 23 (FGF23).

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Dec
1969

Duchenne muscular dystrophy (DMD) is a lethal muscle disease involving progressive loss of muscle regenerative capacity and increased fibrosis. We tested whether epigenetic silencing of the klotho gene occurs in the mdx mouse model of DMD and whether klotho silencing is an important feature of the disease. Our findings show that klotho undergoes muscle-specific silencing at the acute onset of mdx pathology.

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Dec
1969

Klotho, a protein mainly expressed in kidney and cerebral choroid plexus, is a powerful regulator of 1,25(OH)2D3 formation. Klotho-deficient mice (kl/kl) suffer from excessive plasma 1,25(OH)2D3-, Ca(2+)- and phosphate-concentrations, leading to severe soft tissue calcification and accelerated aging. NH4Cl treatment prevents tissue calcification and premature ageing without affecting 1,25(OH)2D3-formation.

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Dec
1969

Reduced homoarginine plasma levels are associated with unfavourable cardiovascular outcome in chronic kidney disease (CKD). Cardiovascular events in CKD are fostered by vascular calcification, an active process promoted by hyperphosphatemia and involving osteo-/chondrogenic transformation of vascular smooth muscle cells (VSMCs). The present study explored the effect of homoarginine on phosphate-induced osteo-/chondrogenic signalling and vascular calcification.

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Dec
1969

Tubulo-interstitial fibrosis is a common, destructive endpoint for a variety of kidney diseases. Fibrosis is well correlated with the loss of kidney function in both humans and rodents. The identification of modulators of fibrosis could provide novel therapeutic approaches to reducing disease progression or severity.

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Dec
1969

Klotho is required for the inhibitory effect of FGF23 on 1,25(OH)2D3 formation and Klotho-hypomorphic mice (kl/kl) suffer from severe tissue calcification due to excessive 1,25(OH)2D3 formation with subsequent increase of Ca2+ and phosphate concentrations and stimulation of osteogenic signaling. The excessive tissue calcification dramatically accelerates aging and leads to premature death of the animals. Osteogenic signaling in those mice is disrupted by treatment with NH4Cl, which prevents tissue calcification and early death of kl/kl mice.

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Apr
2016

αKlotho is a circulating protein that originates predominantly from the kidney and exerts cytoprotective effects in distant sites. We previously showed in rodents that the lung is particularly vulnerable to αKlotho deficiency. Because acute lung injury is a common and serious complication of acute kidney injury (AKI), we hypothesized that αKlotho deficiency in AKI contributes to lung injury.

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Dec
1969

Klotho is a single-pass transmembrane protein predominantly expressed in the kidney. The extracellular domain of Klotho is subject to ectodomain shedding and is released into the circulation as a soluble form. Soluble Klotho is also generated from alternative splicing of the Klotho gene.

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Jan
2016

Klotho, a protein counteracting aging, is a powerful inhibitor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] formation and regulator of mineral metabolism. In klotho hypomorphic (kl/kl) mice, excessive 1,25(OH)2D3 formation leads to hypercalcemia, hyperphosphatemia and vascular calcification, severe growth deficits, accelerated aging and early death. Kl/kl mice further suffer from extracellular volume depletion and hypotension, leading to the stimulation of antidiuretic hormone and aldosterone release.

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Oct
2015

Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2.

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Dec
1969

The reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1) signaling complex is a key regulator of p38 MAPK activity, a major modulator of stress-associated with aging disorders. We recently reported that the ratio of free ASK1 to the complex-bound ASK1 is significantly decreased in Klotho-responsive manner and that Klotho-deficient tissues have elevated levels of free ASK1 which coincides with increased oxidative stress. Here, we tested the hypothesis that: 1) covalent interactions exist among three identified proteins constituting the ASK1 signaling complex; 2) in normal unstressed cells the ASK1, 14-3-3ζ and thioredoxin (Trx) proteins simultaneously engage in a tripartite complex formation; 3) Klotho's stabilizing effect on the complex relied solely on 14-3-3ζ expression and its apparent phosphorylation and dimerization changes.

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Nov
2015

Although the Klotho gene has been recognized as an aging-suppressor gene, the significance of its soluble product, soluble αKlotho (sKlotho), in aging remains to be elucidated. To address this issue, we conducted a single-centered cross-sectional study in a region with a high prevalence of aging. We compared sKlotho levels with the patient characteristics from medical records and laboratory measurements, including fibroblast growth factor 23 (FGF23), intact parathyroid hormone, activated vitamin D3 and factors associated with mineral bone metabolism, in 52 outpatients with a mean age of 78.

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Dec
1969

Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal levels of 8-hydroxy-2-deoxyguanosine, albeit this anti-oxidant defense mechanism has not been locally investigated in the brain. Here, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK pathway regulates stress levels in the brain of these mice and showed that: 1) the ratio of free ASK1 to thioredoxin (Trx)-bound ASK1 is relatively lower in the transgenic brain whereas the reverse is true for the Klotho knockout mice; 2) the reduced p38 activation level in the transgene corresponds to higher level of ASK1-bound Trx, while the KO mice showed elevated p38 activation and lower level of-bound Trx; and 3) that 14-3-3ζ is hyper phosphorylated (Ser-58) in the transgene which correlated with increased monomer forms. In addition, we evaluated the in vivo robustness of the protection by challenging the brains of Klotho transgenic mice with a neurotoxin, MPTP and analyzed for residual neuron numbers and integrity in the substantia nigra pars compacta.

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Jan
2016

Klotho, a protein expressed mainly in the kidney, is required for the inhibitory effect of FGF23 on renal 1,25(OH)2D3 formation. Klotho counteracts vascular calcification and diverse age-related disorders. Klotho-hypomorphic mice (kl/kl) suffer from severe vascular calcification and rapid aging.

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Jan
2016

αKlotho is a multifunctional protein highly expressed in the kidney. Soluble αKlotho is released through cleavage of the extracellular domain from membrane αKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating αKlotho production and handling is incompletely understood, however.

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May
2015

The active form of vitamin D, 1,25(OH)₂D₃, is a powerful regulator of cytosolic Ca(2+)-concentration ([Ca(2+)]i) in a variety of cell types. The formation of 1,25(OH)₂D₃ is inhibited by FGF23, an effect requiring presence of klotho. 1,25(OH)₂D₃ plasma levels are excessive in klotho-deficient mice (kl/kl).

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Feb
2015

Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown.

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Oct
2015

Klotho, a cofactor in suppressing 1,25(OH)2D3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH)2D3, Ca(2+), and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescence-associated molecules Tgfb1, Pai-1, p21, and Glb1.

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May
2015

Cardiac hypertrophy occurs in up to 95% of patients with CKD and increases their risk for cardiovascular death. In the kidney, full-length membranous Klotho forms the coreceptor for fibroblast growth factor 23 (FGF23) to regulate phosphate metabolism. The prevailing view is that the decreased level of Klotho in CKD causes cardiomyopathy through increases in serum FGF23 and/or phosphate levels.

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Jun
2015

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 deficiency-genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD.

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Feb
2015

αKlotho is the prototypic member of the Klotho family and is most highly expressed in the kidney. αKlotho has pleiotropic biologic effects, and in the kidney, its actions include regulation of ion transport, cytoprotection, anti-oxidation and anti-fibrosis. In rodent models of chronic kidney disease (CKD), αKlotho deficiency has been shown to be an early biomarker as well as a pathogenic factor.

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Oct
2014

α-Klotho exerts pleiotropic biological actions. Heterozygous α-Klotho haplo-insufficient mice (kl/+) appear normal at baseline except for age-related changes in the lung, suggesting heightened pulmonary susceptibility to α-Klotho deficiency. We used in vivo and in vitro models to test whether α-Klotho protects lung epithelia against injury.

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Dec
2013

Extracellular phosphate is toxic to the cell at high concentrations. When the phosphate level is increased in the blood by impaired urinary phosphate excretion, premature aging ensues. When the phosphate level is increased in the urine by dietary phosphate overload, this may lead to kidney damage (tubular injury and interstitial fibrosis).

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Jul
2014

Cardiovascular disease remains the single most serious contributor to mortality in chronic kidney disease (CKD). Although conventional risk factors are prevalent in CKD, both cardiomyopathy and vasculopathy can be caused by pathophysiologic mechanisms specific to the uremic state. CKD is a state of systemic αKlotho deficiency.

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May
2014

Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers.

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May
2014

Although epidemiologic associations have been informative, the elucidation of the role of fibroblast growth factor 23 (FGF23) in chronic kidney disease (CKD) requires testing with robust experimental models. Jimbo et al. used animal and cell-culture models to query whether FGF23 is a direct 'vasculotoxin.

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May
2014

Platelets are activated by increased cytosolic Ca(2+) concentration ([Ca(2+)]i) following store-operated calcium entry (SOCE) accomplished by calcium-release-activated calcium (CRAC) channel moiety Orai1 and its regulator STIM1. In other cells, Ca(2+) transport is regulated by 1,25(OH)2 vitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 formation is inhibited by klotho and excessive in klotho-deficient mice (kl/kl).

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Dec
1969


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Jan
2014

Memo is a widely expressed 33-kDa protein required for heregulin (HRG)-, epidermal growth factor (EGF)-, and fibroblast growth factor (FGF)-induced cell motility. Studies in mouse embryonic fibroblasts, wild-type or knockout for Memo, were performed to further investigate the role of Memo downstream of FGFR. We demonstrated that Memo associates with the FGFR signalosome and is necessary for optimal activation of signaling.

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Oct
2013

Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease.

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Nov
2013

Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism.

Nat Rev Nephrol 2013 Nov 18;9(11):650-60. Epub 2013 Jun 18.
Makoto Kuro-o
High concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphate excretion increases serum phosphate level and induces a premature-ageing phenotype. Urinary phosphate levels are increased by dietary phosphate overload and might induce tubular injury and interstitial fibrosis.

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Sep
2013

Dysregulated Ca(2+) homeostasis likely contributes to the etiology of inflammatory bowel disease-associated loss of bone mineral density. Experimental colitis leads to decreased expression of Klotho, a protein that supports renal Ca(2+) reabsorption by stabilizing the transient receptor potential vanilloid 5 (TRPV5) channel on the apical membrane of distal tubule epithelial cells.
Colitis was induced in mice via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) or transfer of CD4(+)interleukin-10(-/-) and CD4(+), CD45RB(hi) T cells.

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