Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through
            <scp>AMPK</scp>
            α‐mediated activation of
            <scp>RUNX</scp>
            2

Chen, Jianglei; Yan, Lin; Sun, Zhongjie

doi:10.1111/acel.12494

Cited by 43 publications

(26 citation statements)

References 45 publications

(70 reference statements)

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“…The histological and IHC analysis was performed as described in our recent studies (Chen, Lin & Sun, 2016; Gao et al., 2016; Lin, Chen & Sun, 2016; Lin & Sun, 2015a,b; Varshney, Ali, Wu & Sun, 2016). For details, see Data S1.…”

Section: Methodsmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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Summary DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.

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Section: Methodsmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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“…In addition to its anti-aging function, α-KL serves an essential role in the phosphatonin FGF23 signaling pathway and secreted KL functions as an endocrine hormone ( 19 ). Previous studies have identified that α-KL is associated with a range of diseases, including periodontitis ( 20 ), cardiovascular disease ( 21 ) and kidney disease ( 18 ). However, the role of α-KL in hemopathies, including anemia, remains unclear.…”

Section: Generation and Function Of Klmentioning

confidence: 99%

α‑klotho and anemia in patients with chronic kidney disease patients: A new perspective (Review)

Peng

2017

Exp Ther Med

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Normocytic normochromic anemia is a common complication of chronic kidney disease (CKD) and is associated with numerous adverse consequences. Certain symptoms previously attributed to CKD are now known to be a consequence of anemia. Anemia contributes to an increased cardiac output, and the development of left ventricular hypertrophy, angina and congestive heart failure, leading to high morbidity and mortality in patients with CKD. The multifunctional α-klotho (KL) protein, which is predominantly expressed in the kidneys, is associated with the occurrence of anemia in patients with CKD. The present review presents current evidence on the potential role of α-KL in renal anemia. Low expression of α-KL appears to improve anemia in patients with CKD, and has been hypothesized to be a compensatory mechanism to attenuate the effects of anemia in patients with CKD. Further understanding of the role of α-KL in renal anemia may offer novel insights into the treatment of patients with CKD complicated with anemia.

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“…Klotho levels in the kidney and blood were lower in patients with CKD [15]. Klotho-deficient mice suffer from a wide variety of age-related disorders as well as tissue calcification, including aortic valve calcification [16, 17]. However, it remains unknown whether Klotho suppresses high Pi-induced osteogenic responses in human AVICs.…”

Section: Introductionmentioning

confidence: 99%

Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9

Yao

et al. 2017

J Mol Med

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Elevated level of blood phosphate (Pi) associated with chronic kidney disease (CKD) is a risk factor of aortic valve calcification. Aortic valve interstitial cells (AVICs) display osteogenic responses to high Pi although the underlying mechanism is incompletely understood. Sox9 is a pro-chondrogenic factor and may play a role in ectopic tissue calcification. Circulating and kidney levels of Klotho are reduced in patients with CKD. We hypothesized that Sox9 mediates high Pi-induced osteogenic responses in human AVICs and that Klotho inhibits the responses. Treatment of human AVICs with high Pi increased protein levels of Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP), and a prolonged exposure to high Pi caused calcium deposition. High Pi induced Sox9 upregulation through PKD and Akt activation. Knockdown of Sox9 essentially abolished the effect of high Pi on the osteogenic responses. Lower Klotho levels were observed in calcified aortic valve tissues. Interestingly, high Pi decreased Klotho levels in AVICs from normal valves, and treatment with recombinant Klotho markedly reduced the effect of high Pi on the levels of Sox9, Runx2, and ALP and suppressed calcium deposition. We conclude that high Pi induces human AVIC osteogenic responses through Sox9. Human AVICs express Klotho, and its levels in AVICs are modulated by high Pi and valvular calcification. Importantly, Klotho suppresses the pro-osteogenic effect of high Pi on human AVICs. These novel findings indicate that modulation of Klotho may have therapeutic potential for mitigation of valvular calcification associated with CKD.

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Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2

Cited by 43 publications

References 45 publications

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

α‑klotho and anemia in patients with chronic kidney disease patients: A new perspective (Review)

Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9

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