Klotho is regulated by transcription factor Sp1 in renal tubular epithelial cells
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BMC Molecular and Cell Biology
RESEARCH ARTICLE
Open Access
Klotho is regulated by transcription factor Sp1 in renal tubular epithelial cells Yan Li, Yong Liu, Kailong Wang, Yinghui Huang, Wenhao Han, Jiachuan Xiong, Ke Yang, Mingying Liu, Tangli Xiao, Chi Liu, Ting He, Xianjin Bi, Jingbo Zhang, Bo Zhang and Jinghong Zhao*
Abstract Background: Klotho is a multifunctional protein, which exists both in a membrane bound and a soluble form. In renal tubules, Klotho is involved in cell senescence, anti-oxidant response, and renal fibrosis, thus regulation of its expression is critical to understand its roles in renal diseases. Indeed, reduced expression was observed in various renal disease. However, the mechanisms underlying transcriptional regulation of the human klotho gene (KL) largely remain unknown. Results: Here we demonstrated that the Klotho expression in human renal tubular epithelial cells (RTECs) was enhanced by overexpression of the transcription factor Sp1. On the contrary, Klotho expression was decreased by Sp1 knockdown. Besides, increased expression of Sp1 alleviated TGF-β1-induced fibrosis in HK-2 cells by inducing Klotho expression. Luciferase reporter assays and chromatin immunoprecipitation assays further identified the binding site of Sp1 was located in − 394 to − 289 nt of the KL promoter, which was further confirmed by mutation analysis. Conclusions: These data demonstrate that KL is a transcriptional target of Sp1 and TGF-β1-induced fibrosis was alleviated by Sp1 in human RTECs by directly modulating Klotho expression, which help to further understand the transcriptional regulation of Klotho in renal disease models. Keywords: Sp1, Klotho, Transcriptional regulation, Renal tubular epithelial cells
Background Klotho (KL) is originally identified by an accidental site defect, which is related to premature multiple organ failure. Owing to alternative splicing, the human KL encodes two forms of proteins, which are predominantly expressed in human renal tubular epithelial cells (RTECs). One exists as a full-length membrane-associated form, whereas the other exists as a secreted form lacking the transmembrane segment and the intracellular domain [1]. The membrane Klotho can form a high-affinity co-receptor with fibroblast growth factor (FGF) receptors for FGF23, and thereby contributes to the signal transduction of FGF23 [2, 3]. The * Correspondence: [email protected] Department of Nephrology, the key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, People’s Republic of China
secreted Klotho is predominantly detected in cerebrospinal fluid and circulation and is involved in the regulation of anti-oxidative capacity, growth factors pathway and ion transport [4–6]. As known, KL is expressed predominantly in kidney, parathyroid gland and choroid plexus [7, 8]. A significantly reduced Klotho was observed in patients with either acute or chronic kid
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