Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis

Zhou, Xiaoli; Chen, Kai; Wang, Yongjun; Schuman, Mariano Luis; Lv, Han; Sun, Zhongjie

doi:10.1681/asn.2015010093

Cited by 43 publications

(21 citation statements)

References 57 publications

(73 reference statements)

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“…The proposed cross-talk between the renin-angiotensin-aldosterone system and the vitamin D-FGF23-Klotho pathways supports the hypothesis that modulation of one system can have positive effects on the other [83, 84], [85]. In this context, a post hoc analysis of the ESCAPE trial in children with CKD (all received fixed dose of ramipril 6 mg/m 2 per day) showed that 25 (OH)-D ≥50 nmol/L was associated with greater preservation of renal function.…”

Section: Klotho Deficiency As a Biomarker For Ckdmentioning

confidence: 56%

Potential application of klotho in human chronic kidney disease

Neyra

2017

Bone

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The extracellular domain of transmembrane alpha-Klotho (αKlotho, hereinafter simply called Klotho) is cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho in the circulation starts to decline early in chronic kidney disease (CKD) stage 2 and urinary Klotho possibly even earlier in CKD stage 1. Therefore soluble Klotho could serve as an early and sensitive marker of kidney function decline. Moreover, preclinical animal data support Klotho deficiency is not just merely a biomarker, but a pathogenic factor for CKD progression and extrarenal CKD complications including cardiovascular disease and disturbed mineral metabolism. Prevention of Klotho decline, re-activation of endogenous Klotho production or supplementation of exogenous Klotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification in CKD. Therefore Klotho is not only a diagnostic and/or prognostic marker for CKD, but the treatment of Klotho deficiency may be a promising strategy to prevent, retard, and decrease the burden of comorbidity in CKD.

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Section: Klotho Deficiency As a Biomarker For Ckdmentioning

confidence: 56%

Potential application of klotho in human chronic kidney disease

Neyra

2017

Bone

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“…7, 27–29 At the end of the experiment, BP was assessed from the arcus aortae via direct cannulation of a carotid artery under anesthesia (1% isoflurane) before euthanasia.…”

Section: Methodsmentioning

confidence: 99%

Activation of SIRT1 Attenuates Klotho Deficiency–Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity

et al. 2016

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Arterial stiffness is an independent risk factor for stroke and myocardial infarction. This study was designed to investigate the role of SIRT1, an important deacetylase, and its relationship with Klotho, a kidney-derived aging-suppressor protein, in the pathogenesis of arterial stiffness and hypertension. We found that the serum level of Klotho was decreased by nearly 45% in patients with arterial stiffness and hypertension. Interestingly, Klotho haplodeficiency caused arterial stiffening and hypertension, as evidenced by significant increases in pulse wave velocity (PWV) and blood pressure (BP) in Klotho-haplodeficient (KL+/−) mice. Notably, the expression and activity of SIRT1 were decreased significantly in aortic endothelial and smooth muscle cells in KL+/− mice, suggesting that Klotho deficiency downregulates SIRT1. Treatment with SRT1720 (15 mg/kg/day, IP), a specific SIRT1 activator, abolished Klotho deficiency-induced arterial stiffness and hypertension in KL+/− mice. Klotho deficiency was associated with significant decreases in activities of AMP-activated protein kinase alpha (AMPKα) and endothelial nitric oxide synthase (eNOS) in aortas, which were abolished by SRT1720. Furthermore, Klotho deficiency upregulated NADPH oxidase activity and superoxide production, increased collagen expression, and enhanced elastin fragmentation in the media of aortas. These Klotho deficiency-associated changes were blocked by SRT1720. In conclusion, this study provides the first evidence that Klotho deficiency downregulates SIRT1 activity in arterial endothelial and smooth muscle cells. Pharmacological activation of SIRT1 may be an effective therapeutic strategy for arterial stiffness and hypertension.

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“…However, the mechanism by which α-klotho affects CYP11B2 and aldosterone synthesis is not clear. The α-klotho deficiency-induced increase in aldosterone is not caused by over activity of the renin-angiotensin system [20]. Moreover, it has been reported that blockade of aldosterone receptors almost abolished klotho deficiencyinduced kidney damage in Kl (+/-) mice [20].…”

Section: Discussionmentioning

confidence: 98%

“…The α-klotho deficiency-induced increase in aldosterone is not caused by over activity of the renin-angiotensin system [20]. Moreover, it has been reported that blockade of aldosterone receptors almost abolished klotho deficiencyinduced kidney damage in Kl (+/-) mice [20]. Further studies are required to characterize the interaction between α-klotho and aldosterone, and its role in the progression of CKD.…”

Section: Discussionmentioning

confidence: 99%

Circulating α-Klotho is Related to Plasma Aldosterone and Its Follow-Up Change Predicts CKD Progression

Qian

Zhong

Yan

et al. 2018

Kidney Blood Press Res

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Background/Aims: We aimed to determine if soluble α-klotho level was an indicator of chronic kidney disease (CKD) progression and whether α-klotho interacted with aldosterone during the course of further renal damage. Methods: 112 adults with stages 1–5 CKD were enrolled into our cohort study. All of the patients were followed up for 6 years (from January 2010 to December 2015). Serum soluble α-klotho and aldosterone were measured at baseline and at 1.5-years follow-up. The primary outcome was the initiation of renal replacement therapy (RRT) and the secondary outcome was the occurrence of cardio-cerebrovascular events. Long-term progression to RRT and cardio-cerebrovascular events in patients was analyzed with a risk-adjusted Cox proportional hazards regression model. Adjustment included age, gender, eGFR, mean arterial pressure, 24-h protein excretion and the change in α-klotho level from baseline at 1.5-years follow-up. Results: Baseline circulating α-klotho levels were positively associated with baseline estimated glomerular filtration rate (eGFR; r = 0.224, p = 0.017), but not age, calcium, phosphate, or parathyroid hormone levels. The change in α-klotho level from baseline at 1.5-years follow-up (p = 0.002) was independently associated with renal replace treatment (RRT) initiation after adjustment for age, gender, eGFR, mean arterial pressure, and 24-h protein excretion in Cox regression analysis. Aldosterone levels were positively associated with CKD stage, and were inversely correlated with circulating α-klotho levels. Conclusion: The change in concentration of soluble α-klotho during the 1.5-years follow-up was an indicator of CKD progression. Renal damage associated with a reduction of α-klotho may involve the upregulation of plasma aldosterone. Future studies are needed to validate our findings, and to investigate the underlying mechanism by which α-klotho and aldosterone may cause renal damage.

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Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis

Cited by 43 publications

References 57 publications

Potential application of klotho in human chronic kidney disease

Potential application of klotho in human chronic kidney disease

Activation of SIRT1 Attenuates Klotho Deficiency–Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity

Circulating α-Klotho is Related to Plasma Aldosterone and Its Follow-Up Change Predicts CKD Progression

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