Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease

Lü, Xiang; Hu, Ming

doi:10.1159/000452880

Cited by 152 publications

(132 citation statements)

References 105 publications

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“…Klotho is antiaging protein that is highly expressed in renal tubular epithelium of normal kidney, which is suppressed in the elderly and in patients with CKD. 112,113 Klotho is present as full-length, transmembrane protein or secreted, soluble form. Both membranous and soluble forms of Klotho can bind with multiple Wnt ligands and represses their target genes transcription.…”

Section: Wnt Signaling and Kidney Diseasesmentioning

confidence: 99%

Wnt Signaling in Kidney Development and Disease

Wang

Zhou

Liu

2018

Progress in Molecular Biology and Translational Science

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Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients.

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Section: Wnt Signaling and Kidney Diseasesmentioning

confidence: 99%

Wnt Signaling in Kidney Development and Disease

Wang

Zhou

Liu

2018

Progress in Molecular Biology and Translational Science

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“…Clinically, uremic cardiomyopathy is characterized by cardiac arrest or sudden death, left ventricular hypertrophy, cardiac fibrosis, congestive heart failure, and so on [4-6]. In addition to traditional risk factors such as smoking, hypertension, diabetes, anemia, and volume overload, Klotho deficiency also plays an important role because soluble Klotho (s-Klotho) is a circulating substance exerting multiple systemic biological actions on distant organs, such as directly protecting cells against a variety of insults including hypoxia, hyperoxia, oxidative stress, and cytotoxic medication and suppressing apoptosis [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Relationship of Serum Soluble Klotho Levels and Echocardiographic Parameters in Patients on Maintenance Hemodialysis

Zhang

Guo

et al. 2019

Kidney Blood Press Res

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Background: Cardiovascular disease is the leading cause of morbidity and mortality in maintenance hemodialysis (MHD) patients. Uremic cardiomyopathy, characterized by myocardial hypertrophy and fibrosis, has a significant contribution to these adverse cardiac outcomes. The protective effect of soluble Klotho (s-Klotho) on myocardial damage was demonstrated in in vitro and animal experiments. However, data from MHD patients is limited. The present study was designed to identify potential correlations between echocardiographic parameters and serum s-Klotho levels in MHD patients. Methods: This is a cross-sectional study involving 105 MHD patients from the Dialysis Center of Capital Medical University affiliated Beijing Friendship Hospital between March and October 2014. The general information for each patient was recorded. Fasting blood samples were collected prior to hemodialysis during the mid-week session in all patients. The echocardiogram and left lateral lumbar spine radiograph were performed after the same mid-week session. The dialysis records for each session within 3 months before the blood tests were documented. According to the quartiles of s-Klotho levels, patients were divided into four groups (Group 1–4). The demographic and clinical characteristics, echocardiographic parameters, and abdominal aortic calcification scores among the groups were compared. Results: The enrolled 105 patients were predominantly male (54.3%) with an average age of 59.9 ± 11.2 years. Previous hemodialysis durations were 76 (42–133) months. Sixteen (15.2%) patients had diabetes mellitus. Mean serum s-Klotho level was 411.83 ± 152.95 pg/mL, and the 25th percentile, 50th percentile, and 75th percentile values of serum s-Klotho levels were 298.9, 412, and 498.2 pg/mL, respectively. Individuals in the bottom quartile of s-Klotho levels (Group 1) had significantly increased interventricular septal thickness (IVST) compared to those in the other three quartiles of s-Klotho levels (Group 1: 1.12 ± 0.16 cm; vs. Group 2: 1.12 ± 0.16 cm, p = 0.008; vs. Group 3: 0.94 ± 0.13 cm, p < 0.001; vs. Group 4: 1.03 ± 0.1 5 cm, p = 0.022). There were significant differences in the ratios of IVST and posterior wall thickness (PWT) between patients of Group 1 and Group 3 (1.12 ± 0.1 2 vs. 1.00 ± 0.1 4, p = 0.004). No significant differences were found for other parameters among the groups. The univariate correlation analyses showed that gender (r = –0.211, p = 0.030), Kt/V urea (r = –0.240, p = 0.014), hypersensitive C reactive protein (hs-CRP) (r = 0.196, p = 0.045), and serum s-Klotho levels (r = –0.260, p = 0.007) significantly correlated with IVST. Ultimately, only hs-CRP and serum s-Klotho levels were entered into a multiple regression model. Conclusions: The present study showed that patients with lower circulating s-Klotho levels were more often associated with larger IVST and greater ratios of IVST and PWT. There was an independent association between s-Klotho and IVST, and lower s-Klotho levels seem to be a potential risk factor of uremic...

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“…The Klotho/FGF23 axis is identified as a target for kidney clinics, and Klotho/FGF23 is a prognostic biomarker for CKD and CVD . The presence of Klotho in vascular walls is unclear; however, all the experiments have shown that Klotho prevents VC development.…”

Section: Discussionmentioning

confidence: 99%

“…The Klotho gene encodes a 130‐kDa single‐channel transmembrane protein with a short cytoplasmic domain (10 amino acids) that is primarily expressed in the kidney . FGF23 was identified as a phosphaturic hormone and mainly produced by osteocytes in the bone . Klotho significantly enhances the ability of FGF23 and functions as a cofactor essential for activation of FGF signaling by FGF23 .…”

Section: Introductionmentioning

confidence: 99%

Klotho/FGF23 axis mediates high phosphate‐induced vascular calcification in vascular smooth muscle cells via Wnt7b/β‐catenin pathway

Chen

Huang

Duan

et al. 2019

The Kaohsiung J of Med Scie

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Vascular calcification (VC) plays as a critical role on cardiovascular disease (CVD) and acts as a notable risk factor in cardiovascular system. Vascular smooth muscle cells (VSMCs) calcification can be triggered by high phosphate treatment; however, the explicit mechanism remains unclear. In the present study, we isolated VSMCs from primary rat artery, applied β‐GP (β‐glycerophosphate) for inducing VSMCs calcification in vitro to explore the mechanism of phosphate‐induced calcification in VSMCs. Alizarin red staining was performed to assess the mineralization in VSMCs. Calcium deposition experiment was taken to evaluate the calcium content. ALP staining was determined to assess the ALP activity. The recombinant adenoviruses were constructed for the overexpression of Klotho and FGF23, respectively. qRT‐PCR and western blot analysis were subjected to measure the expression of Klotho/FGF23 and correlated genes among Wnt7b/β‐catenin pathway. We found that the calcium content was obviously increased and Alizarin red staining was positive in calcification group exposure with high phosphate in a time‐dependent manner. The expression of Klotho and FGF23 was significantly decreased in the calcification group. However, overexpression of Klotho and FGF23 markedly reversed VSMCs calcification stimulating with high phosphate treatment. Moreover, Wnt7b/β‐catenin inhibitor DKK1 could partly attenuate the effect of high phosphate on calcified VSMCs. These findings demonstrated that Klotho/FGF23 axis could modulate high phosphate‐induced VSMCs calcification via Wnt7b/β‐catenin signaling pathway. Our findings unravel that Klotho/FGF23‐ Wnt7b/β‐catenin axis functions as a crucial role in the VSMCs calcification.

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Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease

Cited by 152 publications

References 105 publications

Wnt Signaling in Kidney Development and Disease

Wnt Signaling in Kidney Development and Disease

Relationship of Serum Soluble Klotho Levels and Echocardiographic Parameters in Patients on Maintenance Hemodialysis

Klotho/FGF23 axis mediates high phosphate‐induced vascular calcification in vascular smooth muscle cells via Wnt7b/β‐catenin pathway

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