Transcription factor Kruppel-like factor 5 positively regulates the expression of AarF domain containing kinase 4
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ORIGINAL ARTICLE
Transcription factor Kruppel-like factor 5 positively regulates the expression of AarF domain containing kinase 4 Xi Chen1 · Shuang Liu1 · Jiahe Chen1 · Xinyu Wang1 · Guoping Zhou1 Received: 27 May 2020 / Revised: 26 September 2020 / Accepted: 30 September 2020 © Springer Nature B.V. 2020
Abstract AarF domain containing kinase 4 (ADCK4) is identified as a candidate gene associated with hereditary nephrotic syndrome (NS). Kruppel-like factor 5 (KLF5) is reported to promote podocyte survival by blocking the ERK/p38 MAPK pathways. Both ADCK4 and KLF5 are involved in the occurrence and development of podocyte disease, but their interaction remains unclear. Firstly, we found that the mRNA levels of ADCK4 and KLF5 decreased in NS patients, and both levels showed an obvious linear relationship. Secondly, we cloned the ADCK4 promoter region and examined its promoter activity in Hela, A549, and HEK 293 cell lines. Deletion analysis showed that the region − 116/− 4 relative to the transcriptional start site (TSS) was the core region of ADCK4 promoter. Thirdly, mutation analysis showed that putative binding sites for KLF5 contributed to the ADCK4 promoter activity. In HEK293 cells, we found that KLF5 upregulated the mRNA and protein levels of ADCK4. Finally, our chromatin immunoprecipitation assay found that KLF5 could bind to the specific region of ADCK4 promoter. These results showed that KLF5 can positively regulate the transcriptional activity of ADCK4. Keywords AarF domain containing kinase 4 · Kruppel-like factor 5 · Transcriptional regulation · Promoter · Nephrotic syndrome
Introduction Nephrotic syndrome (NS) is the most common primary glomerular disorder in children [1, 2]. NS is caused by the collpase of glomerular filtration barrier, the integrity of which relies on podocytes largely [3]. All the already-reported 24 genes associated with NS are localized in podocytes, which confirms the importance of podocytes in protecting the barrier [4]. Podocyte-associated gene mutations act in the molecular pathogenesis of glomerular filtration disorder, thereby providing new therapeutic approaches [5]. AarF domain containing kinase 4 (ADCK4) spans 12 kb on chromosome 19q13.1. Ashraf et al. identified mutations of ADCK4 as a single-gene cause of hereditary NS by using exome sequencing [6]. The gene ADCK4 is involved in the biosynthesis pathway of CoQ10, and the CoQ10 levels Xi Chen and Shuang Liu have contributed equally to this work. * Guoping Zhou [email protected] 1
Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
decreased in patients with ADCK4 mutations. Furthermore, knockdown of ADCK4 can reduce podocyte migration, and this disorder can be reversed by the supplement of CoQ10 [6, 7]. It has been reported that CoQ10 supplementation is effective in reducing proteinuria, which indicated that the treatment may ameliorate ADCK4-associated renal disease [8–12]. Therefore, a better understanding of ADCK4 can supply novel therapeutical
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