The Experts below are selected from a list of 2055 Experts worldwide ranked by ideXlab platform
Makoto Kuro-o - One of the best experts on this subject based on the ideXlab platform.
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The secreted Klotho Protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice.
European journal of pharmacology, 2012Co-Authors: Tso Hsiao Chen, Makoto Kuro-o, Cheng Hsien Chen, Yuh Mou Sue, Yen Cheng Chen, Chung Yi ChengAbstract:Klotho was identified as the responsible gene in a mutant mouse line whose disruption results in a variety of premature aging-related phenotypes. Nonetheless, the related mechanisms were still unknown. Many studies report that dietary phosphate restriction and genetic ablation of vitamin D pathways indirectly reverse premature aging processes in these mice. Furthermore, transgenic overexpression of Klotho in mice extends their life span through inhibition of insulin and IGF1 signaling. We found that intraperitoneal injection of recombinant soluble Klotho Protein at dose of 0.02 mg/kg every other day effectively extends the life span of kl/kl mice by 17.4%. Soluble Klotho administration also ameliorated premature aging-related phenotype, such as growth retardation, premature thymus involution and vascular calcification, and effectively enhanced urinary phosphate excretion in kl/kl mice. Klotho treatment attenuated renal fibrosis through down-regulation of transforming growth factor-β signaling as well as reduced cellular senescence through down-regulation of p21-cip1 mRNA levels. In addition, soluble Klotho treatment significantly reduced both renal and aorta calcium deposits. In conclusion, our study shows the therapeutic potential of soluble Klotho Protein to treat age-related disorders in mice.
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Klotho.
Pflugers Archiv : European journal of physiology, 2009Co-Authors: Makoto Kuro-oAbstract:The Klotho gene was identified as an "aging-suppressor" gene in mice that accelerates aging when disrupted and extends life span when overexpressed. It encodes a single-pass transmembrane Protein and is expressed primarily in renal tubules. The extracellular domain of Klotho Protein is secreted into blood and urine by ectodomain shedding. The two forms of Klotho Protein, membrane Klotho and secreted Klotho, exert distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for FGF23, a bone-derived hormone that induces phosphate excretion into urine. Mice lacking Klotho or FGF23 not only exhibit phosphate retention but also display a premature-aging syndrome, revealing an unexpected link between phosphate metabolism and aging. Secreted Klotho functions as a humoral factor that regulates activity of multiple glycoProteins on the cell surface, including ion channels and growth factor receptors such as insulin/insulin-like growth factor-1 receptors. Potential contribution of these multiple activities of Klotho Protein to aging processes is discussed.
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Klotho and aging
Biochimica et Biophysica Acta, 2009Co-Authors: Makoto Kuro-oAbstract:The Klotho gene encodes a single-pass transmembrane Protein that forms a complex with multiple fibroblast growth factor (FGF) receptors and functions as an obligatory co-receptor for FGF23, a bone-derived hormone that induces negative phosphate balance. Defects in either Klotho or Fgf23 gene expression cause not only phosphate retention but also a premature-aging syndrome in mice, unveiling a potential link between phosphate metabolism and aging. In addition, the extracellular domain of Klotho Protein is clipped on the cell surface and secreted into blood stream, potentially functioning as an endocrine factor. The secreted Klotho Protein has a putative sialidase activity that modifies glycans on the cell surface, which may explain the ability of secreted Klotho Protein to regulate activity of multiple ion channels and growth factors including insulin, IGF-1, and Wnt. Secreted Klotho Protein also protects cells and tissues from oxidative stress through a mechanism yet to be identified. Thus, the transmembrane and secreted forms of Klotho Protein have distinct functions, which may collectively affect aging processes in mammals.
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Klotho as a regulator of oxidative stress and senescence.
Biological Chemistry, 2008Co-Authors: Makoto Kuro-oAbstract:Abstract The Klotho gene functions as an aging-suppressor gene that extends life span when overexpressed and accelerates aging-like phenotypes when disrupted in mice. The Klotho gene encodes a single-pass transmembrane Protein that binds to multiple fibroblast growth factor (FGF) receptors and functions as a co-receptor for FGF23, a bone-derived hormone that suppresses phosphate reabsorption and vitamin D biosynthesis in the kidney. In addition, the extracellular domain of Klotho Protein is shed and secreted, potentially functioning as a humoral factor. The secreted Klotho Protein can regulate multiple growth factor signaling pathways, including insulin/IGF-1 and Wnt, and the activity of multiple ion channels. Klotho Protein also protects cells and tissues from oxidative stress, yet the precise mechanism underlying these activities remains to be determined. Thus, understanding of Klotho Protein function is expected to provide new insights into the molecular basis for aging, phosphate/vitamin D metabolism, cancer and stem cell biology.
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Klotho Protein protects against endothelial dysfunction.
Biochemical and biophysical research communications, 1998Co-Authors: Yuichiro Saito, Yoshio Ohyama, Masahiko Kurabayashi, Takahiro Yamagishi, Tetsuya Nakamura, Hiroki Aizawa, Tatsuo Suga, Matsumura Yutaka, Hiroaki Masuda, Makoto Kuro-oAbstract:Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established Klotho mouse which causes age-related disorders including arteriosclerosis. However, no information on endothelial function of Klotho mouse or the physiological role of Klotho Protein as a circulating factor is available. In this report, we demonstrate that 50% effective dose of aortic relaxation in response to acetylcholine in heterozygous Klotho mice is significantly greater (4 x 10(-5) M) than in wild-type mice (8 x 10(-6) M, n = 7, p 1 x 10(-5) M) as compared with wild-type mice (1 x 10(-7) M, n = 7, p < 0.05). Nitric oxide metabolites (NO-2 and NO-3) in urine are significantly lower in heterozygous Klotho mice (142 +/- 16 nmol/day) than wild-type mice (241 +/- 28 nmol/day, n = 13, p < 0.05). Parabiosis between wild-type and heterozygous Klotho mice results in restoration of endothelial function in heterozygous Klotho mice. We conclude that the Klotho Protein protects the cardiovascular system through endothelium-derived NO production by humoral pathways.
Toshio Ogihara - One of the best experts on this subject based on the ideXlab platform.
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Klotho Protein promotes adipocyte differentiation.
Endocrinology, 2006Co-Authors: Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Masashi Ikushima, Yoshihiro Maekawa, Junsuke Ohta, Iwao Kida, Toshio OgiharaAbstract:Mice with homozygous disruption of the Klotho exhibit multiple age-related disorders and have barely detectable amounts of white adipose tissue. Although Klotho expression in cultured adipocytes has been reported, little is known about its function in adipocytes. In the present study, we investigated the role of Klotho on adipocyte differentiation. Adipocyte differentiation was induced by incubation of confluent 3T3-L1 cells with insulin, dexamethasone, and 1-methyl-3-isobutyl-xanthin. Klotho-siRNA and expression vector were produced for Klotho suppression and overexpression, respectively. Klotho Protein was purified for determination of the hormonal effect of Klotho. Klotho mRNA and Protein expression increased up to the 3rd d of differentiation. A peroxisome proliferator-activated receptor-gamma agonist increased Klotho expression during the early period of adipocyte differentiation. The mRNA expression of adipocyte differentiation markers, such as CCAAT/enhancer-binding Protein (C/EBP)alpha, C/EBPbeta, C/EBPdelta, peroxisome proliferator-activated receptor-gamma, and fatty acid binding Protein 4, was decreased by Klotho suppression, and increased 1.9- to 3.8-fold by Klotho overexpression. The results of Oil Red O staining also suggested that Klotho overexpression promoted adipocyte differentiation. Klotho Protein stimulation resulted in a 2.4- to 4.6-fold increase in mRNA expression of differentiation markers compared with control, and the time course depended on adipocyte induction status. Western blot analysis showed that Protein levels of C/EBPalpha and C/EBPdelta were increased by Klotho Protein stimulation. These results suggest that Klotho works as a hormonal factor to promote adipocyte differentiation in the early days, during the period of transient proliferation in the differentiation process, and that Klotho may play an essential role in adipocyte differentiation.
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Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells
Biochemical and biophysical research communications, 2005Co-Authors: Masashi Ikushima, Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Yoshihiro Maekawa, Junsuke Ohta, Iwao Kida, Koichi Yamamoto, Toshio OgiharaAbstract:Abstract Klotho-mutated mice manifest multiple age-related disorders that are observed in humans. A recent study suggested that Klotho Protein might function as an anti-aging hormone in mammals. Because it has been reported that apoptosis and senescence in vascular endothelial cells are closely related to the progression of atherosclerosis, we investigated Klotho’s ability to interfere with apoptosis and cellular senescence in human umbilical vascular endothelial cells (HUVEC). Klotho overexpression decreased H2O2-induced apoptosis in COS-1 cells and Jurkat cells. Klotho Protein also reduced H2O2- and etoposide-induced apoptosis in HUVEC. Caspase-3 and caspase-9 activity was lower in Klotho-treated HUVEC than in control cells. Senescence-associated β-gal staining showed that Klotho Protein interferes with H2O2-induced premature cellular senescence. The expression of p53 and p21 was lower in Klotho-treated cells. Our study suggests that Klotho acts as a humoral factor to reduce H2O2-induced apoptosis and cellular senescence in vascular cells.
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Klotho Protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1α-hydroxylase gene expression
Endocrine, 2004Co-Authors: Michio Imai, Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Masashi Ikushima, Junsuke Ohta, Iwao Kida, Naomichi Matsukawa, Xu Rui, Toshio OgiharaAbstract:Homozygous Klotho mutant (kl −/−) mice exhibit a variety of phenotypes resembling human aging, including arteriosclerosis, infertility, skin atrophy, osteoporosis, and short life span. Calcium abnormality, one of the phenotypes in kl −/− mice, is thought to be due to the elevated gene expression of 25-hydroxyvitamin D3 1α-hydroxylase in the kidney. We studied 25-hydroxyvitamin D3 1α-hydroxylase gene expression using a Klotho plasmid that we had previously constructed for Klotho Protein production. It was found that Klotho Protein medium upregulated cAMP and the PKC pathway, and suppressed 25-hydroxyvitamin D3 1α-hydroxylase in kidney cells. However, both cAMP and PKC are known to elevate 25-hydroxyvitamin D3 1α-hydroxylase gene expression, therefore, another unknown calcium regulation pathway using Klotho Protein medium might exist. Furthermore, we found that activation of the PKC pathway by Klotho was observed only in the kidney and testis, where the Klotho gene is expressed, although activation of the cAMP pathway was observed in any kind of cell. These data suggest that calcium regulation through 25-hydroxyvitamin D3 1α-hydroxylase by Klotho depends on non-cAMP and a non-PKC pathway and that the Klotho Protein may have different signaling pathways, depending on the Klotho gene expression in different cells and organs.
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Upregulation of cAMP is a new functional signal pathway of Klotho in endothelial cells.
Biochemical and biophysical research communications, 2003Co-Authors: Jin Yang, Hiromi Rakugi, Junsuke Ohta, Iwao Kida, Yo-ichi Nabeshima, Michio Imai, Naomichi Matsukawa, Michiko Nagai, Keisuke Fukuo, Toshio OgiharaAbstract:We measured angiotensin I-converting enzyme (ACE) activity in a human endothelial cell to characterize the intracellular signal pathways of Klotho. COS-1 cells transfected with naked mouse membrane-form Klotho plasmid DNA (pCAGGS-Klotho) translated proper Klotho Protein. This translated Klotho Protein was secreted into the culture medium. Furthermore, ACE activity in human umbilical vein endothelial cells (HUVEC) was upregulated when HUVEC were co-cultured with COS-1 cells that were pre-transfected with pCAGGS-Klotho. The conditioned medium from COS-1 cells pre-transfected with pCAGGS-Klotho also dose-dependently upregulated ACE in HUVEC. In addition, the conditioned medium induced time- and dose-dependent enhancement of cAMP production in HUVEC. Rp-cAMP, an inhibitor of cAMP-dependent Protein kinase A (PKA), inhibited the upregulation of ACE by Klotho Protein. Our results suggest that mouse membrane-form Klotho Protein acts as a humoral factor to increase ACE activity in HUVEC via a cAMP-PKA-dependent pathway. These findings may provide a new insight into the mechanism of Klotho Protein.
Hiromi Rakugi - One of the best experts on this subject based on the ideXlab platform.
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Klotho Protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway.
Geriatrics & gerontology international, 2011Co-Authors: Yoshihiro Maekawa, Masashi Ikushima, Mitsuru Ohishi, Koichi Yamamoto, Osamu Yasuda, Ryosuke Oguro, Hiroko Yamamoto-hanasaki, Yuji Tatara, Yasushi Takeya, Hiromi RakugiAbstract:Aim: Mice that carry the Klotho mutation (KL-/-) manifest diverse age-related disorders similar to those observed in humans. Thus, the Klotho Protein might function as an anti-aging hormone in mammals. Recently, we reported that Klotho recombinant Protein attenuated apoptosis and cellular senescence in endothelial cells, but the mechanism remained unclear. Here, we designed an in vitro study to test whether inhibitors of extracellular signal-regulated kinase and mitogen-activated kinase kinase could affect Klotho regulation of apoptosis and cellular senescence. Methods: Cellular senescence was investigated in human umbilical vein endothelial cells treated with or without Klotho recombinant Protein, and with or without inhibitors of mitogen-activated kinases. Senescence was quantified by staining with senescence-associated β-galactosidase and by evaluating western blots probed for phosphorylation of mitogen-activated kinases. Apoptosis was assayed on western probed for p53, p21, and caspase-3 and -9. Results: The Klotho recombinant Protein induced transient phosphorylation of mitogen-activated kinases within a few minutes. Application of inhibitors of mitogen-activated kinases attenuated the ability of Klotho to interfere with apoptosis and senescence in endothelial cells. Conclusion: This study demonstrated that Klotho attenuated cellular apoptosis and senescence in vascular cells via mitogen-activated kinase kinase and extracellular signal-regulated kinase pathways. Geriatr Gerontol Int 2011; 11: 510–516.
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Klotho Protein promotes adipocyte differentiation.
Endocrinology, 2006Co-Authors: Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Masashi Ikushima, Yoshihiro Maekawa, Junsuke Ohta, Iwao Kida, Toshio OgiharaAbstract:Mice with homozygous disruption of the Klotho exhibit multiple age-related disorders and have barely detectable amounts of white adipose tissue. Although Klotho expression in cultured adipocytes has been reported, little is known about its function in adipocytes. In the present study, we investigated the role of Klotho on adipocyte differentiation. Adipocyte differentiation was induced by incubation of confluent 3T3-L1 cells with insulin, dexamethasone, and 1-methyl-3-isobutyl-xanthin. Klotho-siRNA and expression vector were produced for Klotho suppression and overexpression, respectively. Klotho Protein was purified for determination of the hormonal effect of Klotho. Klotho mRNA and Protein expression increased up to the 3rd d of differentiation. A peroxisome proliferator-activated receptor-gamma agonist increased Klotho expression during the early period of adipocyte differentiation. The mRNA expression of adipocyte differentiation markers, such as CCAAT/enhancer-binding Protein (C/EBP)alpha, C/EBPbeta, C/EBPdelta, peroxisome proliferator-activated receptor-gamma, and fatty acid binding Protein 4, was decreased by Klotho suppression, and increased 1.9- to 3.8-fold by Klotho overexpression. The results of Oil Red O staining also suggested that Klotho overexpression promoted adipocyte differentiation. Klotho Protein stimulation resulted in a 2.4- to 4.6-fold increase in mRNA expression of differentiation markers compared with control, and the time course depended on adipocyte induction status. Western blot analysis showed that Protein levels of C/EBPalpha and C/EBPdelta were increased by Klotho Protein stimulation. These results suggest that Klotho works as a hormonal factor to promote adipocyte differentiation in the early days, during the period of transient proliferation in the differentiation process, and that Klotho may play an essential role in adipocyte differentiation.
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Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells
Biochemical and biophysical research communications, 2005Co-Authors: Masashi Ikushima, Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Yoshihiro Maekawa, Junsuke Ohta, Iwao Kida, Koichi Yamamoto, Toshio OgiharaAbstract:Abstract Klotho-mutated mice manifest multiple age-related disorders that are observed in humans. A recent study suggested that Klotho Protein might function as an anti-aging hormone in mammals. Because it has been reported that apoptosis and senescence in vascular endothelial cells are closely related to the progression of atherosclerosis, we investigated Klotho’s ability to interfere with apoptosis and cellular senescence in human umbilical vascular endothelial cells (HUVEC). Klotho overexpression decreased H2O2-induced apoptosis in COS-1 cells and Jurkat cells. Klotho Protein also reduced H2O2- and etoposide-induced apoptosis in HUVEC. Caspase-3 and caspase-9 activity was lower in Klotho-treated HUVEC than in control cells. Senescence-associated β-gal staining showed that Klotho Protein interferes with H2O2-induced premature cellular senescence. The expression of p53 and p21 was lower in Klotho-treated cells. Our study suggests that Klotho acts as a humoral factor to reduce H2O2-induced apoptosis and cellular senescence in vascular cells.
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Klotho Protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1α-hydroxylase gene expression
Endocrine, 2004Co-Authors: Michio Imai, Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Masashi Ikushima, Junsuke Ohta, Iwao Kida, Naomichi Matsukawa, Xu Rui, Toshio OgiharaAbstract:Homozygous Klotho mutant (kl −/−) mice exhibit a variety of phenotypes resembling human aging, including arteriosclerosis, infertility, skin atrophy, osteoporosis, and short life span. Calcium abnormality, one of the phenotypes in kl −/− mice, is thought to be due to the elevated gene expression of 25-hydroxyvitamin D3 1α-hydroxylase in the kidney. We studied 25-hydroxyvitamin D3 1α-hydroxylase gene expression using a Klotho plasmid that we had previously constructed for Klotho Protein production. It was found that Klotho Protein medium upregulated cAMP and the PKC pathway, and suppressed 25-hydroxyvitamin D3 1α-hydroxylase in kidney cells. However, both cAMP and PKC are known to elevate 25-hydroxyvitamin D3 1α-hydroxylase gene expression, therefore, another unknown calcium regulation pathway using Klotho Protein medium might exist. Furthermore, we found that activation of the PKC pathway by Klotho was observed only in the kidney and testis, where the Klotho gene is expressed, although activation of the cAMP pathway was observed in any kind of cell. These data suggest that calcium regulation through 25-hydroxyvitamin D3 1α-hydroxylase by Klotho depends on non-cAMP and a non-PKC pathway and that the Klotho Protein may have different signaling pathways, depending on the Klotho gene expression in different cells and organs.
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Upregulation of cAMP is a new functional signal pathway of Klotho in endothelial cells.
Biochemical and biophysical research communications, 2003Co-Authors: Jin Yang, Hiromi Rakugi, Junsuke Ohta, Iwao Kida, Yo-ichi Nabeshima, Michio Imai, Naomichi Matsukawa, Michiko Nagai, Keisuke Fukuo, Toshio OgiharaAbstract:We measured angiotensin I-converting enzyme (ACE) activity in a human endothelial cell to characterize the intracellular signal pathways of Klotho. COS-1 cells transfected with naked mouse membrane-form Klotho plasmid DNA (pCAGGS-Klotho) translated proper Klotho Protein. This translated Klotho Protein was secreted into the culture medium. Furthermore, ACE activity in human umbilical vein endothelial cells (HUVEC) was upregulated when HUVEC were co-cultured with COS-1 cells that were pre-transfected with pCAGGS-Klotho. The conditioned medium from COS-1 cells pre-transfected with pCAGGS-Klotho also dose-dependently upregulated ACE in HUVEC. In addition, the conditioned medium induced time- and dose-dependent enhancement of cAMP production in HUVEC. Rp-cAMP, an inhibitor of cAMP-dependent Protein kinase A (PKA), inhibited the upregulation of ACE by Klotho Protein. Our results suggest that mouse membrane-form Klotho Protein acts as a humoral factor to increase ACE activity in HUVEC via a cAMP-PKA-dependent pathway. These findings may provide a new insight into the mechanism of Klotho Protein.
Masashi Ikushima - One of the best experts on this subject based on the ideXlab platform.
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Klotho Protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway.
Geriatrics & gerontology international, 2011Co-Authors: Yoshihiro Maekawa, Masashi Ikushima, Mitsuru Ohishi, Koichi Yamamoto, Osamu Yasuda, Ryosuke Oguro, Hiroko Yamamoto-hanasaki, Yuji Tatara, Yasushi Takeya, Hiromi RakugiAbstract:Aim: Mice that carry the Klotho mutation (KL-/-) manifest diverse age-related disorders similar to those observed in humans. Thus, the Klotho Protein might function as an anti-aging hormone in mammals. Recently, we reported that Klotho recombinant Protein attenuated apoptosis and cellular senescence in endothelial cells, but the mechanism remained unclear. Here, we designed an in vitro study to test whether inhibitors of extracellular signal-regulated kinase and mitogen-activated kinase kinase could affect Klotho regulation of apoptosis and cellular senescence. Methods: Cellular senescence was investigated in human umbilical vein endothelial cells treated with or without Klotho recombinant Protein, and with or without inhibitors of mitogen-activated kinases. Senescence was quantified by staining with senescence-associated β-galactosidase and by evaluating western blots probed for phosphorylation of mitogen-activated kinases. Apoptosis was assayed on western probed for p53, p21, and caspase-3 and -9. Results: The Klotho recombinant Protein induced transient phosphorylation of mitogen-activated kinases within a few minutes. Application of inhibitors of mitogen-activated kinases attenuated the ability of Klotho to interfere with apoptosis and senescence in endothelial cells. Conclusion: This study demonstrated that Klotho attenuated cellular apoptosis and senescence in vascular cells via mitogen-activated kinase kinase and extracellular signal-regulated kinase pathways. Geriatr Gerontol Int 2011; 11: 510–516.
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Klotho Protein promotes adipocyte differentiation.
Endocrinology, 2006Co-Authors: Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Masashi Ikushima, Yoshihiro Maekawa, Junsuke Ohta, Iwao Kida, Toshio OgiharaAbstract:Mice with homozygous disruption of the Klotho exhibit multiple age-related disorders and have barely detectable amounts of white adipose tissue. Although Klotho expression in cultured adipocytes has been reported, little is known about its function in adipocytes. In the present study, we investigated the role of Klotho on adipocyte differentiation. Adipocyte differentiation was induced by incubation of confluent 3T3-L1 cells with insulin, dexamethasone, and 1-methyl-3-isobutyl-xanthin. Klotho-siRNA and expression vector were produced for Klotho suppression and overexpression, respectively. Klotho Protein was purified for determination of the hormonal effect of Klotho. Klotho mRNA and Protein expression increased up to the 3rd d of differentiation. A peroxisome proliferator-activated receptor-gamma agonist increased Klotho expression during the early period of adipocyte differentiation. The mRNA expression of adipocyte differentiation markers, such as CCAAT/enhancer-binding Protein (C/EBP)alpha, C/EBPbeta, C/EBPdelta, peroxisome proliferator-activated receptor-gamma, and fatty acid binding Protein 4, was decreased by Klotho suppression, and increased 1.9- to 3.8-fold by Klotho overexpression. The results of Oil Red O staining also suggested that Klotho overexpression promoted adipocyte differentiation. Klotho Protein stimulation resulted in a 2.4- to 4.6-fold increase in mRNA expression of differentiation markers compared with control, and the time course depended on adipocyte induction status. Western blot analysis showed that Protein levels of C/EBPalpha and C/EBPdelta were increased by Klotho Protein stimulation. These results suggest that Klotho works as a hormonal factor to promote adipocyte differentiation in the early days, during the period of transient proliferation in the differentiation process, and that Klotho may play an essential role in adipocyte differentiation.
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Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells
Biochemical and biophysical research communications, 2005Co-Authors: Masashi Ikushima, Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Yoshihiro Maekawa, Junsuke Ohta, Iwao Kida, Koichi Yamamoto, Toshio OgiharaAbstract:Abstract Klotho-mutated mice manifest multiple age-related disorders that are observed in humans. A recent study suggested that Klotho Protein might function as an anti-aging hormone in mammals. Because it has been reported that apoptosis and senescence in vascular endothelial cells are closely related to the progression of atherosclerosis, we investigated Klotho’s ability to interfere with apoptosis and cellular senescence in human umbilical vascular endothelial cells (HUVEC). Klotho overexpression decreased H2O2-induced apoptosis in COS-1 cells and Jurkat cells. Klotho Protein also reduced H2O2- and etoposide-induced apoptosis in HUVEC. Caspase-3 and caspase-9 activity was lower in Klotho-treated HUVEC than in control cells. Senescence-associated β-gal staining showed that Klotho Protein interferes with H2O2-induced premature cellular senescence. The expression of p53 and p21 was lower in Klotho-treated cells. Our study suggests that Klotho acts as a humoral factor to reduce H2O2-induced apoptosis and cellular senescence in vascular cells.
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Klotho Protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1α-hydroxylase gene expression
Endocrine, 2004Co-Authors: Michio Imai, Yukana Chihara, Hiromi Rakugi, Kazuhiko Ishikawa, Masashi Ikushima, Junsuke Ohta, Iwao Kida, Naomichi Matsukawa, Xu Rui, Toshio OgiharaAbstract:Homozygous Klotho mutant (kl −/−) mice exhibit a variety of phenotypes resembling human aging, including arteriosclerosis, infertility, skin atrophy, osteoporosis, and short life span. Calcium abnormality, one of the phenotypes in kl −/− mice, is thought to be due to the elevated gene expression of 25-hydroxyvitamin D3 1α-hydroxylase in the kidney. We studied 25-hydroxyvitamin D3 1α-hydroxylase gene expression using a Klotho plasmid that we had previously constructed for Klotho Protein production. It was found that Klotho Protein medium upregulated cAMP and the PKC pathway, and suppressed 25-hydroxyvitamin D3 1α-hydroxylase in kidney cells. However, both cAMP and PKC are known to elevate 25-hydroxyvitamin D3 1α-hydroxylase gene expression, therefore, another unknown calcium regulation pathway using Klotho Protein medium might exist. Furthermore, we found that activation of the PKC pathway by Klotho was observed only in the kidney and testis, where the Klotho gene is expressed, although activation of the cAMP pathway was observed in any kind of cell. These data suggest that calcium regulation through 25-hydroxyvitamin D3 1α-hydroxylase by Klotho depends on non-cAMP and a non-PKC pathway and that the Klotho Protein may have different signaling pathways, depending on the Klotho gene expression in different cells and organs.
Naoki Kashihara - One of the best experts on this subject based on the ideXlab platform.
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Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice
Clinical and Experimental Nephrology, 2016Co-Authors: Hiroyuki Kadoya, Minoru Satoh, Tamaki Sasaki, Yoshisuke Haruna, Naoki KashiharaAbstract:Background Expression of Klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that Klotho Protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy. Methods Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant Klotho, and calpain activity and proinflammatory cytokine expressions were measured. Results We found that Klotho Protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of Klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant Klotho, which also suppressed the induction of proinflammatory cytokines. Conclusion Our data suggest Klotho Protein protects against diabetic nephropathy through multiple pathways.
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Overexpression of Klotho Protein modulates uninephrectomy-induced compensatory renal hypertrophy by suppressing IGF-I signals
Biochemical and biophysical research communications, 2011Co-Authors: Hajime Nagasu, Minoru Satoh, Atsunori Kuwabara, Daisuke Yorimitsu, Kengo Kidokoro, Yuko Nishi, Naruya Tomita, Tamaki Sasaki, Naoki KashiharaAbstract:The Klotho gene is highly expressed in the distal convoluted tubule of the kidney, while its encoded Protein has many physiological and pathophysiological renal roles. We investigated the effect of Klotho Protein on physiological compensatory renal hypertrophy after nephrectomy in Klotho transgenic (KLTG) mice. Renal hypertrophy was suppressed in KLTG mice compared with wild-type mice, and this was associated with suppression of insulin growth factor-1 (IGF-1) signaling by Klotho Protein. In vitro, IGF-1 signaling was suppressed in human proximal tubular cells transfected with the Klotho plasmid. Our data suggest that Klotho modulates compensatory renal hypertrophy after nephrectomy via suppression of the IGF-1 signaling pathway, indicating a novel physiological role for Klotho Protein in the kidney.