The Role of Klotho on Vascular Calcification and Endothelial Function in Chronic Kidney Disease

Vervloet, Marc G.; Adema, Aaltje Y.; Larsson, Tobias E.; Massy, Ziad A.

doi:10.1016/j.semnephrol.2014.09.003

Cited by 44 publications

(30 citation statements)

References 81 publications

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“…It may be biologically plausible to replenish soluble α-Klotho or increase the expression of membrane-bound α-Klotho in patients with CKD, as CKD is a state of α-Klotho deficiency and α-Klotho exerts its multiple organ-protective function in the kidney, vessel wall, and heart [52,99]. A better understanding of the pathophysiological roles of soluble α-Klotho and the safety of administering soluble α-Klotho in human will drive us to perform clinical studies that focus on the protective effect of α-Klotho on VC in CKD.…”

Section: Implication For Treatment Of Vc In Ckd-mbdmentioning

confidence: 99%

Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho

Yamada

Giachelli

2017

Bone

238

196

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Vascular calcification (VC) is highly prevalent in aging, diabetes mellitus, and chronic kidney disease (CKD). VC is a strong predictor of cardiovascular morbidity and mortality in the CKD population. Complex pathological mechanisms are involved in the development of VC, including osteochondrogenic differentiation and apoptosis of vascular smooth muscle cells, instability and release of extracellular vesicles loaded calcium and phosphate, and elastin degradation. Elevated serum phosphate is a late manifestation of CKD, and has been shown to accelerate mineral deposition in both the vessel wall and heart valves. α-Klotho and fibroblast growth factor 23 (FGF23) are emerging factors in CKD-mineral and bone disorder (CKD-MBD) and are thought to be involved in the pathogenesis of uremic VC. There are discordant reports regarding the biomedical effects of FGF23 on VC. In contrast, mounting evidence supports a well-supported protective role for α-Klotho on VC. Further studies are warranted to elucidate potential roles of FGF23 and α-Klotho in VC and to determine where and how they are synthesized in normal and disease conditions. A thorough systemic evaluation of the biomedical interplay of phosphate, FGF23, and α-Klotho may potentially lead to new therapeutic options for patients with CKD-MBD.

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Section: Implication For Treatment Of Vc In Ckd-mbdmentioning

confidence: 99%

Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho

Yamada

Giachelli

2017

Bone

238

196

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“…Apart from traditional risk factors, the high CV morbidity and mortality in CKD have been linked to CKD-specific mechanisms of vascular calcification through modulation of the endothelium–vascular smooth muscle network (Hu et al, 2014; Vervloet, Adema, Larsson, & Massy, 2014). Calcium and phosphate play an important role in the initiation of osteochondrogenic changes of cellular elements in the arterial wall, and also in the final common pathway of alleged ectopic bone formation (Vervloet et al, 2014).…”

Section: αKlotho Deficiency In CV Disease In Ckdmentioning

confidence: 99%

αKlotho and Chronic Kidney Disease

Neyra¹,

Hu²

2016

Klotho

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Alpha-Klotho (αKlotho) protein is encoded by the gene, Klotho, and functions as a coreceptor for endocrine fibroblast growth factor-23. The extracellular domain of αKlotho is cleaved by secretases and released into the circulation where it is called soluble αKlotho. Soluble αKlotho in the circulation starts to decline in chronic kidney disease (CKD) stage 2 and urinary αKlotho in even earlier CKD stage 1. Therefore soluble αKlotho is an early and sensitive marker of decline in kidney function. Preclinical data from numerous animal experiments support αKlotho deficiency as a pathogenic factor for CKD progression and extrarenal CKD complications including cardiac and vascular disease, hyperparathyroidism, and disturbed mineral metabolism. αKlotho deficiency induces cell senescence and renders cells susceptible to apoptosis induced by a variety of cellular insults including oxidative stress. αKlotho deficiency also leads to defective autophagy and angiogenesis and promotes fibrosis in the kidney and heart. Most importantly, prevention of αKlotho decline, upregulation of endogenous αKlotho production, or direct supplementation of soluble αKlotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiac function and morphometry, and alleviation of vascular calcification in CKD. Therefore in rodents, αKlotho is not only a diagnostic and prognostic marker for CKD but the enhancement of endogenous or supplement of exogenous αKlotho are promising therapeutic strategies to prevent, retard, and decrease the comorbidity burden of CKD.

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“…The extracellular domain of klotho can be cleaved and released into extracellular fluids including plasma (14), where soluble klotho (s-klotho) is detectable via ELISA techniques (15). Circulating klotho is considered to be involved in preservation of endothelial function and arterial wall integrity and hence may be protective against endothelial dysfunction and arteriosclerosis (16), reduced vascular elasticity or calcification (17;18). Recent in vivo findings point towards direct cardioprotective effects of s-klotho (19;20).…”

Section: Introductionmentioning

confidence: 99%

“…A small human study showed that decreased klotho was an independent determinant of arterial stiffness as measured by pulse wave velocity (21). It is noteworthy that klotho also interacts with calcium and phosphate homeostasis which per se influences cardiovascular health (16). Moreover, it is intriguing to speculate about the presence of reciprocal effects between klotho and FGF23.…”

Section: Introductionmentioning

confidence: 99%