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LncRNA ZEB1-AS1 Was Suppressed by p53 for Renal Fibrosis in Diabetic Nephropathy.

ABSTRACT: The role of p53 in renal fibrosis is still controversial, and its underlying mechanisms remain not clear. Here, we showed that the pharmacological inhibition and genetic deletion of p53 in proximal tubular cells can attenuate renal dysfunction, tubular epithelial disruption, and interstitial fibrosis in db/db and STZ-induced diabetic nephrology (DN) mice. In human renal proximal tubule (human kidney 2 [HK-2]) cells, inhibition of p53 by PIF reduced the high glucose (HG)-induced extracellular matrix (ECM) accumulation and reversed the inhibitory effect of HG on mRNA expression levels of lncRNA zinc finger E-box binding homeobox1-antisense RNA 1 (ZEB1-AS1) and ZEB1. Interestingly, our results demonstrated that both lncRNA ZEB1-AS1 and ZEB1 exhibited an anti-fibrotic role, while ZEB1 is positively regulated by lncRNA ZEB1-AS1 during HG treatment. Mechanistically, lnc ZEB1-AS1 bound directly to H3K4 methyltransferase myeloid and lymphoid or mixed-lineage leukemia 1 (MLL1) and promoted H3K4me3 histone modification on ZEB1 promoter, which was reduced by HG treatment. ChIP analysis indicated the binding of p53 to the promoter region of lnc ZEB1-AS1. Furthermore, the findings were verified by the kidney biopsy samples from patients with DN. Taken all together, our results suggest that p53 may be a therapeutic target for renal fibrosis in DN.

SUBMITTER: Wang J

PROVIDER: S-EPMC6095953 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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lncRNA ZEB1-AS1 Was Suppressed by p53 for Renal Fibrosis in Diabetic Nephropathy.

Wang Juan J Pan Jian J Li Huiling H Long Jie J Fang Fang F Chen Junxiang J Zhu Xuejin X Xiang Xudong X Zhang Dongshan D

Molecular therapy. Nucleic acids 20180731

The role of p53 in renal fibrosis is still controversial, and its underlying mechanisms remain not clear. Here, we showed that the pharmacological inhibition and genetic deletion of p53 in proximal tubular cells can attenuate renal dysfunction, tubular epithelial disruption, and interstitial fibrosis in db/db and STZ-induced diabetic nephrology (DN) mice. In human renal proximal tubule (human kidney 2 [HK-2]) cells, inhibition of p53 by PIF reduced the high glucose (HG)-induced extracellular mat ...[more]

PMID: 30121551

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Project description:Long noncoding RNA (lncRNAs) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported in diabetic nephropathy (DN) about its effect on podocyte function and cell heat shock induced by hyperglycemia. However, the biological mechanism of MALAT1 regulating DN fibrosis needs further study. In this study, SD rats were administrated with streptozotocin (STZ) to establish a diabetes model. In vitro, human renal tubular epithelial cells (HK-2 and 293T) were treated with high glucose (HG). Here, we found that MALAT1 was upregulated in renal tissues of diabetic rats and HG-treated cells, and HG treatment promoted cell proliferation and invasion. MALAT1 overexpression aggravated protein levels of collagen I (col I), collagen IV (col IV), fibronectin (FN), and laminin (LN) in HK-2 cells, while MALAT1 knockdown exerted the opposite effect. Moreover, the luciferase reporter gene and pull-down assays demonstrated that MALAT1 interacted with miR-2355-3p. The miR-2355-3p level was downregulated in diabetic rats and HG-treated cells, and MALAT1 overexpression inhibited the miR-2355-3p level. Bioinformatics prediction and luciferase reporter gene assay revealed that interleukin 6 signal transducer (IL6ST) was a target of miR-2355-3p. In addition, miR-2355-3p overexpression attenuated fibrosis-related gene levels in HG-treated cells by inhibiting IL6ST expression and inactivating the recombinant signal transducer and activator of the transcription 3 (STAT3) signaling pathway. Knockdown of miR-2355-3p reversed the inhibitory effect of MALAT1 knockdown on IL6ST, col I, col IV, FN, and LN protein levels in HG-induced cells. Overexpression of MALAT1 aggravated cell damage in HG-induced cells via the miR-2355-3p/IL6ST/STAT3 signaling pathway. Finally, enhanced renal fibrosis and kidney tissue damage were observed in diabetic rats. In conclusion, MALAT1 overexpression may enhance renal fibrosis in diabetic rats and cell damage in HG-induced HK-2 cells via the miR-2355-3p/IL6ST axis, which provides a new perspective of DN treatment.

Dataset Information

LncRNA ZEB1-AS1 Was Suppressed by p53 for Renal Fibrosis in Diabetic Nephropathy.

Publications

lncRNA ZEB1-AS1 Was Suppressed by p53 for Renal Fibrosis in Diabetic Nephropathy.

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