Krϋppel-like factors (KLFs) in renal physiology and disease

Rane, Madhavi J.; Zhao, Yuguang; Cai, Lu

doi:10.1016/j.ebiom.2019.01.021

Cited by 120 publications

(104 citation statements)

References 77 publications

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“…Genes associated with promoting proliferation and fibrosis such as Grem1, Grem2 [24,25], and Ctgf were significantly upregulated in the kidney cortices of diabetic mice; however, the expression of these genes was downregulated following treatment with rosiglitazone. Furthermore, increasing attention has been given to the potential role that Kruppel-like factors (KLFs) have in kidney disease, especially in diabetic nephropathy [26,27]. Specifically, the profibrotic KLF10 and KLF11 and the proinflammatory KLF13 [28,29] have been shown to be significantly upregulated in DN, yet, in our study, rosiglitazone treatment served to reverse this overexpression, which may underline the new renoprotective mechanism of rosiglitazone, and further investigations are needed to confirm their role in DN.…”

Section: Discussionmentioning

confidence: 64%

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Zhang

Zhou

et al. 2020

BioMed Research International

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Diabetic nephropathy (DN) is characterized by metabolic disorder and inflammation. However, the regulatory effects that long noncoding RNAs (lncRNAs) have on the pathogenesis of DN and on the efficacy of rosiglitazone treatment have yet to be clearly defined. Herein, we performed unbiased RNA sequencing to characterize the transcriptomic profiles in db/db diabetic mouse model with or without rosiglitazone treatment that served to improve the phenotypes of DN. Moreover, RNA-seq profiling revealed that the development of DN caused an upregulation in the expression of 1176 mRNAs and a downregulation in the expression of 1010 mRNAs compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with rosiglitazone. Further, 88 upregulated and 68 downregulated lncRNAs were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with rosiglitazone. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARc, are related to inflammatory and metabolic processes. From bioinformatics analysis, lncRNA-AI838599 emerged as a novel molecular mechanism for rosiglitazone treatment in DN through TNFα-NFκb pathway. ese findings may indicate a new molecular regulatory approach for the development of DN therapeutic agents.

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Section: Discussionmentioning

confidence: 64%

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Zhang

Zhou

et al. 2020

BioMed Research International

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“…(Samarakoon et al, 2013;Harskamp et al, 2016). TGF-β1 also induces phosphorylation and acetylation of p53 and promote formation of p53/Smad3 complexes during renal fibrosis (Higgins et al, 2018;Rane et al, 2019). By contrast, BMP signaling via Smad1/5/8 complex is able to counter regulate TGFβ/Smad-mediated renal fibrosis (Weiskirchen et al, 2009;Meng et al, 2013;Munoz-Felix et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Diverse Role of TGF-β in Kidney Disease

Liu

Huang

et al. 2020

Front. Cell Dev. Biol.

170

132

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“…7) uncover novel epigenomic mechanisms for the activation of these pathways by CRC factors in Ewing sarcoma. While TCF4 and NKX2-2 have not been involved in these pathways in any cell type, KLF15 is intriguingly reported to inhibit the AKT and MAPK signaling pathways in normal skeletal muscle, cardiomyocytes and kidney (58–60). It thus appears the regulatory effects of KLF15 on these signaling pathways are cell-type dependent, possibly due to the expression pattern of KLF15 target genes are cell-type specific.…”

Section: Discussionmentioning

confidence: 99%

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi

Zheng

Jiang

et al. 2020

Preprint

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29Core regulatory circuitry (CRC)-dependent transcriptional network is critical for 30 developmental tumors in children and young adults carrying few gene mutations. 31 Ewing sarcoma resembles these developmental cancers in terms of having both 87 few genomic alterations and a single epigenomic driver, we postulated that such 88 oncogenic CRC model might exist in Ewing sarcoma, to cooperate with the 89 transcriptional function of EWS-FLI1. The current study was aimed to identify 90 and characterize this CRC apparatus in Ewing sarcoma, and to elucidate its 91 functional significance in this cancer. 92 93 94 5 / 46 Results 95 96 We recently characterized the super-enhancer landscape in Ewing sarcoma and 97 confirmed the essential role of EWS-FLI1 in regulating the epigenome of this 98 cancer (11). As introduced earlier, considering that CRC is particularly important 99 for childhood developmental cancers having few genomic lesions, we postulated 100 that such CRC model might also contribute to regulating Ewing sarcoma 101 transcriptome through either cooperating with or mediating the function of EWS-102 FLI1. To test this hypothesis, we first sought to identify mathematically master 103 TFs with high inter-connectivity through binding to their super-enhancers by 104 motif scanning using our established method (18, 24, 25). Because of the central 105 role of EWS-FLI1 in establishing the enhancer landscape in Ewing sarcoma, we 106 made significant modifications of the method by requiring that all candidate TFs 107 have both EWS-FLI1 binding motif and binding peaks in their assigned super-108 enhancers. We initially focused on the A673 cell line, since it is a well-109 characterized Ewing sarcoma line with available H3K27ac and EWS-FLI1 ChIP-110 Seq results (7). As a result, a small set (n=9) of CRC candidates were identified 111 (Fig. 1A), including NKX2-2 and FOS which are known functional cooperators 112 of EWS-FLI1 (7, 26). Because CRC factors have high and specific expression in 113 their corresponding cell types, we interrogated the Cancer Cell Line Encyclopedia 114 (CCLE) dataset and noted that, compared with other 5 CRC candidates (NFATC2, 115 FOS, IRF2, ZBTB7B and MEF2D, Supplement Fig. 1), the expression of 4 116 6 / 46 candidate TFs (KLF15, NKX2-2, TCF4 and RREB1) showed restricted 117 expression pattern in Ewing sarcoma cell lines (defined as top 5 among all cell 118 types, Fig. 1B). However, it should be noted that the specificity of RREB1 119 expression was overall poor, as most cancer types had comparable mRNA levels. Identification of CRC under the regulation of EWS-FLI1 in Ewing sarcoma 120As a parallel analysis, Pearson correlation coefficient of the mRNA levels of 121 these 9 candidates was determined, considering the co-regulatory relationship 122 between CRC members. Notably, the same set of 4 factors (KLF15, NKX2-2, 123 TCF4 and RREB1) displayed strong positive correlations with each other (Fig. 124 1C). In contrast, this correlation pattern was much weaker in other non-Ewing 125 sarco...

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Krϋppel-like factors (KLFs) in renal physiology and disease

Cited by 120 publications

References 77 publications

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Diverse Role of TGF-β in Kidney Disease

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

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