Abstract
Klotho (KL) expression is down-regulated in the renal tissues of chronic kidney disease (CKD) animal models and patients with end-stage renal disease. The putative role of KL promoter hypermethylation in the progression of CKD remains unclear. The present study aimed to determine renal and peripheral blood mononuclear cells (PBMC) levels of KL promoter methylation and analyze their relationship with clinical and histological severity in patients with CKD. Using bisulfite pyrosequencing, renal and PBMC levels of KL promoter methylation were quantified in 47 patients with CKD. 47 nephrectomy specimens of patients with renal cell carcinoma and 48 PBMC specimens of healthy volunteers were used as renal tissue and PBMC controls, respectively. Renal expression of KL protein was assayed by immunohistochemistry staining. Receiver operating characteristic (ROC) curve was used to identify the optimal cut-off value of PBMC KL promoter methylation level for renal KL promoter hypermethylation. Higher levels of KL promoter methylation were observed in renal tissue and PBMC in patients with CKD compared with controls (8.79±3.24 vs. 5.17±1.11%, P<0.001; 7.20±2.79 vs. 3.27±0.79%, P<0.001). In these patients, renal KL methylation level correlated inversely with renal KL immunostaining intensity (ρ=-0.794, P<0.001). Estimated glomerular filtration rate correlated inversely with renal and PBMC levels of KL promoter methylation (r=-0.829, P<0.001; r=-0.645, P<0.001), while tubulointerstistial fibrosis score correlated positively (ρ=0.826, P<0.001; ρ=0.755, P<0.001). PBMC KL promoter methylation level correlated positively with renal KL promoter methylation level in patients with CKD (r=0.787, P<0.001). In ROC curve, the area under curve was 0.964 (P<0.001) and the optimal cut-off value was 5.83% with a sensitivity of 93.8% and specificity of 86.7% to predict renal KL promoter hypermethylation. The degree of KL promoter methylation is associated with clinical and histological severity of CKD. PBMC KL promoter methylation level may act as a potential biomarker of renal KL promoter hypermethylation.
Highlights
Klotho (KL) is an antiaging gene, which encodes a singlepass transmembrane protein that forms a complex with multiple fibroblast growth factor 23 (FGF23) receptors
Among 47 patients with chronic kidney disease (CKD), KL promoter was hypermethylated in renal tissue of patients (68.09%) and peripheral blood mononuclear cells (PBMC) of patients (70.21%)
KL promoter of renal tissue and PBMC control showed no characteristics of hypermethylation
Summary
Klotho (KL) is an antiaging gene, which encodes a singlepass transmembrane protein that forms a complex with multiple fibroblast growth factor 23 (FGF23) receptors. KL is most abundant in the renal tubules [1]. KL knockout mice (KL-/-) develop a syndrome resembling patients with chronic kidney disease (CKD), such as shortened lifespan, hyperphosphatemia, and multiple accelerated age-related disorders including diffusive artery calcification [2]. Recent studies have shown that KL could function as a renoprotective factor [3,4]. KL expression is decreased in the renal tissues of CKD animal models and patients with end-stage renal disease [3,5]. KL expression can be inhibited by chronic circulating stress factors, including oxidative stress, inflammation, uremic toxins and disordered metabolic conditions which are common in uremic status [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
