Anti-oxidative effect of Klotho on endothelial cells through cAMP activation

Rakugi, Hiromi; Matsukawa, Naomichi; Ishikawa, Kazuhiko; Yang, Jin; Imai, Michio; Ikushima, Masashi; Maekawa, Yoshihiro; Kida, Iwao; Miyazaki, Jun‐ichi; Ogihara, Toshio

doi:10.1007/s12020-007-0016-9

Cited by 92 publications

(72 citation statements)

References 38 publications

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“…6 Several studies have shown that Klotho may protect against vascular damage through the regulation of nitric oxide release. 6,34 Furthermore, Klotho can confer resistance against oxidative stress involved in the patho- Figure 3 (Continued). Klotho deficiency accelerates the development of calcification, promotes osteo/chondrocytic transformation and loss of smooth muscle phenotype in HA-SMCs exposed to calcifying stress, in vitro.…”

Section: Discussionmentioning

confidence: 99%

Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23

et al. 2012

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“…There may be a crosstalk between klotho and the renin-angiotensin-aldosterone system, as vascular cells express Cyp11b2 and are capable of producing aldosterone (53)(54)(55)(56)(57). Aldosterone may further promote the osteochondrogenic remodeling of vascular smooth muscle cells by downregulating klotho and thereby mediating FGF23 resistance (6,57), nonetheless, following aldosterone treatment, HAoSMCs still respond to FGF23 treatment, which counteracts the effects of aldosterone.…”

Section: Figurementioning

confidence: 99%

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

et al. 2013

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Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH) 2 D 3 ] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease. We show here that the mineralocorticoid receptor antagonist spironolactone reduced vascular and soft tissue calcification and increased the life span of kl/kl mice, without significant effects on 1,25(OH) 2 D 3 , FGF23, calcium, and phosphate plasma concentrations. Spironolactone also reduced the expression of osteoinductive Pit1 and Tnfa mRNA, osteogenic transcription factors, and alkaline phosphatase (Alpl) in calcified tissues of kl/kl mice. In human aortic smooth muscle cells (HAoSMCs), aldosterone dose-dependently increased PIT1 mRNA expression, an effect paralleled by increased expression of osteogenic transcription factors and enhanced ALP activity. The effects of aldosterone were reversed by both spironolactone treatment and PIT1 silencing and were mitigated by FGF23 cotreatment in HAoSMCs. In conclusion, aldosterone contributes to vascular and soft tissue calcification, an effect due, at least in part, to stimulation of spironolactone-sensitive, PIT1-dependent osteoinductive signaling.

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“…Klotho protects ECs from oxidative stressinduced apoptosis by upregulating the expression of the antioxidant enzyme, manganese superoxide dismutase. [79][80][81] Moreover, Klotho maintains endothelial integrity by regulating Ca 2+ influx in ECs. 82 Concerning the action of FGF23 on ED, we recently demtion mode (ie, intermittent vs. continuous).…”

Section: Animal Studiesmentioning

confidence: 99%

Vascular Toxicity of Phosphate in Chronic Kidney Disease

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Kamel

et al. 2014

Circ J

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In epidemiological studies of CKD patients and the general population, high phosphate levels are associated with CV disease (CVD). The association is even observed in early-stage CKD and is independent of other traditional CV risk factors. 5, 6 Along with other factors, hyperphosphatemia is involved in the development of vascular calcification (VC) and endothelial dysfunction (ED), 7-9 both of which are major nontraditional CV risk factors for CKD. Phosphate is able to act either directly on these parameters or indirectly via the FGF23/Klotho and PTH axes (Figure 1).We review the various effects of hyperphosphatemia on CV parameters, with a focus on its emerging role in ED. The efficacy of current therapies for improving phosphate-related CV outcomes is also discussed. Direct Effects of Phosphate on CV Calcification and ED Epidemiological and Interventional StudiesVC is deposition of calcium/phosphate, mostly as apatite, in the blood vessels, myocardium and cardiac valves. Calcification of both the intima and media occurs in CKD, 10 resulting in the stiffness of the large arteries (as evidenced by a higher pulse wave velocity) and thus promotion of CV morbidity/ mortality. The results of several epidemiological studies have highlighted an association between serum phosphate levels and VC in stage 5D CKD patients, 11,12 in early-stage CKD patients and in the general population (in whom serum phosphate levels are still within the normal range). 13, 14 Indeed, 2 elegant prospective studies of large cohorts of hosphate, principally provided by food, is involved in many physiological processes: it buffers the intracellular pH, ensures the stability of the skeleton and contributes to many essential biological functions (eg, DNA synthesis, cell membrane phospholipids, energy metabolism and intracellular signaling pathways that are regulated by phosphorylation/dephosphorylation).The physiological concentration of phosphate (0.8-1.5 mmol/L) is tightly regulated by, among others, the fibroblast growth factor 23 (FGF23)/Klotho axis, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D). 1 In chronic kidney disease (CKD), the progressive loss of functional nephrons induces retention of phosphate, which in turn leads to (1) an increase in calcium/phosphate products and (2) FGF23 synthesis. With the aim of preventing hyperphosphatemia, FGF23 decreases circulating levels of calcitriol, thus inhibiting intestinal phosphate and calcium absorption. PTH, the overexpression of which is triggered by hypocalcemia, stimulates bone resorption for the primary purpose of restoring calcemia but in doing so it increases phosphatemia and thus the calcium/phosphate products. During the course of CKD, Klotho's downregulation in both the parathyroid gland and the kidney results in the loss of FGF23 being able to respectively (1) decrease PTH expression and (2) inhibit renal phosphate reabsorption. In late-stage CKD, the few remaining functional nephrons are no longer able to eliminate phosphate and a vicious circle (referred ...

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Anti-oxidative effect of Klotho on endothelial cells through cAMP activation

Cited by 92 publications

References 38 publications

Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23

Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

Vascular Toxicity of Phosphate in Chronic Kidney Disease

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