MiR‐92b‐3p is Induced by Advanced Glycation End Products and Involved in the Pathogenesis of Diabetic Nephropathy

Abstract

Purpose. The current study aims to examine the effects of advanced glycation end products (AGEs) on the microRNA (miRNA) expression profile in the kidney tissues of rats. Methods. Wistar rats were randomly divided into three equal experiment groups: the AGE group, the RSA group, and the control group. The rats in the AGE group and the RSA group were administered with advanced glycation end products (AGEs) and rat serum albumin (RSA) via the tail vein, respectively, whereas the control group received PBS. Total RNA was prepared from the rat kidney tissues, and the miRNA expression profiles in different experiment groups were compared by microarray analysis. The expression levels of selected differential miRNAs were verified by RT-qPCR. Target gene prediction was conducted using algorithms such as TargetScan, miRanda, and PICTar. Functional analysis was performed to determine the putative biological roles of the validated miRNAs. Results. The microarray study revealed 451 upregulated and 320 downregulated miRNAs in the AGE group compared with the RSA group (p<0.05). Seven miRNAs, including miR-21-5p, miR-92b-3p, miR-140-3p, miR-196a-5p, miR-181b-5p, miR-186-5p, and miR-192-5p, were screened and verified using RT-qPCR, of which, the change of miR-92b-3p was the most obvious according to the miRNA expression different multiple and p value. Furthermore, the expression trend of miR-92b-3p measured by RT-qPCR was shown to be consistent with the microarray results. Bioinformatics analysis and luciferase reporter assay identified Smad7 was a direct target of miR-92b-3p. Both immunohistochemical and western blotting showed that Smad7 expression was significantly suppressed in the kidney tissues from the AGE group compared with the control and RSA groups. Conclusion. The results of the current study suggested that miR-92b-3p could mediate AGE-induced development of renal abnormalities through targeting Smad7 in rats with DN.

Differential expression of microRNAs associated with neurodegenerative diseases and diabetic nephropathy in protein l‐isoaspartyl methyltransferase‐deficient mice

“…Moreover, in DN patients or model mice and high glucose (HG)‐induced DN cellular model, miR‐30c (Gao et al, 2020), (J. Wang et al, 2016), miR‐30e (Zhao, Jia, et al, 2017), miR‐24 (H. Liu, Wang, et al, 2020), miR‐25 (Fu et al, 2010; H. Li et al, 2017), miR‐34a (X. Zhang et al, 2016), miR‐34c (Y. Zhao, Yin, et al, 2017), and miR‐423 (Xu, Zhang, et al, 2018) were also downregulated and its overexpression could promote the proliferation of renal cells and inhibit EMT by targeting Janus kinase‐1 (JAK1), connective tissue growth factor (CTGF), glioma pathogenesis related‐2 (GLIPR‐2), fibroblast growth factor 11 (FGF11), NADPH oxidase 4 (NOX4), the Notch signaling pathway and Snail1‐TGF‐ β 1 pathway, respectively, ultimately preventing renal fibrosis of DNs. However, miR‐34a (Xue et al, 2018; L. Zhang et al, 2014) and miR‐92b (Wang et al, 2020) were upregulated in the kidneys of DN mice or HG‐induced DN cellular model, which was related to glomerular hypertrophy, GAS1‐mediated mesangial cells proliferation, and SIRT1‐mediated fibrosis. Similarly, miR‐25 was found to be decreased in kidney tissues from patients with DN.…”

MiR‐92b‐3p regulates oxygen and glucose deprivation–reperfusion‐mediated apoptosis and inflammation by targeting TRAF3 in PC12 cells

“…MiR‐92b‐3p targets tuberous sclerosis complex 1 (TSC1) to regulate primordial follicle assembly in neonatal mouse ovaries (Li et al., 2019). Phosphatase and tensin homologue (PTEN) and Smad7 are direct targets of miR‐92b‐3p in various cells (Li, Li et al., 2013; Song et al., 2016b; Wang et al., 2020). PTEN plays a critical role in neural development and differentiation, and miR‐92a targets PTEN to promote neurite outgrowth in PC12 cells (Zou et al., 2015).…”

MicroRNA‐210 repression facilitates advanced glycation end‐product (AGE)‐induced cardiac mitochondrial dysfunction and apoptosis via JNK activation

“…Several correlations between miRNA dysregulation and pathological manifestations triggered by diabetes‐associated AGE have been elucidated in various studies 50–52 . The expression of miR‐451, miR‐21, miR‐377, and miR‐192 is known to be associated with AGE‐induced complications in the kidneys 53–56 . miR‐210 has been reported as a hypoxia‐sensitive miRNA, and its overexpression can protect cardiac cells from hypoxia‐induced apoptosis 57 .…”

“…[50][51][52] The expression of miR-451, miR-21, miR-377, and miR-192 is known to be associated with AGE-induced complications in the kidneys. [53][54][55][56] miR-210 has been reported as a hypoxia-sensitive miRNA, and its overexpression can protect cardiac cells from hypoxiainduced apoptosis. 57 Furthermore, two important factors, iron-sulfur cluster scaffold homolog and cytochrome c oxidase assembly protein (COX10), which are involved in the mitochondrial electron transport chain and the tricarboxylic acid cycle, have been reported as potential targets of miR-210, indicating the potential modulation of miR-210 on mitochondrial function.…”