Abstract
BackgroundKlotho 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.ResultsHere 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.ConclusionsThese 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.
Highlights
Klotho is a multifunctional protein, which exists both in a membrane bound and a soluble form
We investigated whether Sp1 could affect Klotho expression and TGF-β1-induced fibrosis in human renal tubular epithelial cells (RTECs)
Overexpression of Sp1 dose-dependently induced Klotho expression in human kidney cells To examine the specific involvement of Sp1 in regulating Klotho expression, a Sp1 expression plasmid was transfected into HK-2 cells to introduce overexpression of Sp1 and Klotho expression was measured both at protein and mRNA levels
Summary
Klotho is a multifunctional protein, which exists both in a membrane bound and a soluble form. Reduced expression was observed in various renal disease. The human KL encodes two forms of proteins, which are predominantly expressed in human renal tubular epithelial cells (RTECs). 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]. A significantly reduced Klotho was observed in patients with either acute or chronic kidney disease (CKD) [9, 10]. Varieties of physiological and pathological factors contribute to the regulation of KL expression [4, 9, 10], but the transcriptional regulatory mechanism underlying the KL expression is not entirely clear
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