MiR-92b-3p is induced by advanced glycation end products and involved in the pathogenesis of diabetic nephropathy

Background. The current study aims to explore the effects of advanced glycation end products (AGEs) on the microRNA (miRNA) expression profile in kidney tissues in a murine diabetic nephropathy (DN) model, and to investigate the possible underlying mechanisms. Methods. Wister 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 AGEs and rat serum albumin (RSA) via the tail vein, respectively, whereas those in the control group received no injection. Following the extraction of total RNA from the murine kidney tissues, miRNA profiling was performed using a miRNA microarray to determine the global differences in miRNA expression between the three experiment groups. The identified panel of aberrantly expressed miRNA candidates were subsequently validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Bioinformatics analysis was performed to identify the target genes and enriched signaling pathway for the validated miRNAs. Results. Compared with RSA group, miR-7d-3p, miR-92b-3p, miR-181b-5p and miR-196c-5p were found to be significantly up-regulated in the AGE group, whereas miR-7a-1-3p, miR-186-5p, miR-192-5P, miR-196b-5p and miR-345-5p were shown to be down-regulated (p<0.05). Among the nine miRNA candidates, miR-92b-3p was validated by qRT-PCR analysis. Subsequent bioinformatic study indicated that SMAD7 could be a potential downstream gene target of miR-92b-3p. Both immunohistochemical staining and western blotting showed that SMAD7 expression was significantly suppressed in the kidney tissues harvested from the AGE group compared to those from the control and the RSA group. Discussion. The results of the current study revealed a correlation between increased renal level of miR-92b-3p and elevated serum level of AGEs in a murine model of DN.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/6050874 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Li-ping Wang ◽

Jia-nan Geng ◽

Bo Sun ◽

Cheng-bo Sun ◽

Yan Shi ◽

...

Keyword(s):

Advanced Glycation End Products ◽

Mirna Expression ◽

Expression Profiles ◽

Rat Kidney ◽

Luciferase Reporter ◽

Control Group ◽

Age Group ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

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.

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Advanced Glycation End Products and Diabetic Nephropathy

American Journal of Therapeutics ◽

10.1097/01.mjt.0000178769.52610.69 ◽

2005 ◽

Vol 12 (6) ◽

pp. 562-572 ◽

Cited By ~ 70

Author(s):

Merlin C Thomas ◽

Josephine M Forbes ◽

Mark E Cooper

Keyword(s):

Diabetic Nephropathy ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

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Advanced Glycation End Products and the Pathogenesis of Diabetic Nephropathy

Contributions to Nephrology - Type-2 Diabetic Nephropathy in Japan ◽

10.1159/000060150 ◽

2001 ◽

pp. 30-35 ◽

Cited By ~ 7

Author(s):

S.-i. Yamagishi ◽

M. Takeuchi ◽

Z. Makita

Keyword(s):

Diabetic Nephropathy ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

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Endogenous Secretory Receptor for Advanced Glycation End Products Protects Endothelial Cells from AGEs Induced Apoptosis

BioMed Research International ◽

10.1155/2018/8216578 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Guomin Yang ◽

Yinqiong Huang ◽

Xiaohong Wu ◽

Xiahong Lin ◽

Jinting Xu ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Advanced Glycation End Products ◽

Proinflammatory Cytokine ◽

Enzyme Linked Immunosorbent Assay ◽

Advanced Glycation ◽

Expression Levels ◽

Qrt Pcr ◽

Glycation End Products ◽

End Products

Endogenous secretory receptor for advanced glycation end products (esRAGE) binds extracellular RAGE ligands and blocks RAGE activation on the cell surface, protecting endothelial cell function. However, the underlying mechanism remains unclear. Endothelial cells overexpressing the esRAGE gene were generated using a lentiviral vector. Then, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to assess esRAGE mRNA and protein levels, respectively. Hoechst-PI double staining was used to assess apoptosis. Western blot and qRT-PCR were used to assess the expression levels of apoptosis-related factors and the proinflammatory cytokine NF-кB. Compared with the control group, AGEs significantly induced endothelial cell apoptosis, which was significantly reduced by esRAGE overexpression. Incubation with AGEs upregulated the proapoptotic factor Bax and downregulated the antiapoptotic factor Bcl-2. Overexpression of esRAGE reduced Bax expression induced by AGEs and increased Bcl-2 levels. Furthermore, AGEs increased the expression levels of proinflammatory cytokine NF-кB, which were reduced after esRAGE overexpression. esRAGE protects endothelial cells from AGEs associated apoptosis, by downregulating proapoptotic (Bax) and inflammatory (NF-кB) factors and upregulating the antiapoptotic factor Bcl-2.

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Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-Ay/Ta mice

Metabolism ◽

10.1016/j.metabol.2006.08.026 ◽

2007 ◽

Vol 56 (2) ◽

pp. 160-167 ◽

Cited By ~ 65

Author(s):

Mitsuo Tanimoto ◽

Tomohito Gohda ◽

Shigeru Kaneko ◽

Shinji Hagiwara ◽

Maki Murakoshi ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Type 2 Diabetic

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Advanced glycation end-products in diabetic nephropathy

Nephrology Dialysis Transplantation ◽

10.1093/ndt/11.supp5.91 ◽

1996 ◽

Vol 11 (supp5) ◽

pp. 91-94 ◽

Cited By ~ 15

Author(s):

S. Sugiyama ◽

T. Miyata ◽

K. Horie ◽

Y. Iida ◽

M. Tsuyuki ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

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AGE, RAGE and Diabetic Nephropathy

European Endocrinology ◽

10.17925/ee.2012.08.02.84 ◽

2010 ◽

Vol 8 (2) ◽

pp. 84

Author(s):

MaÏté Daroux ◽

Nicolas Grossin ◽

Eric Boulanger ◽

◽

...

Keyword(s):

Chronic Kidney Disease ◽

Diabetic Nephropathy ◽

Kidney Disease ◽

Advanced Glycation End Products ◽

Specific Treatment ◽

Therapeutic Approaches ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Immunohistochemical Studies

Diabetes is a disease that is present worldwide and which is associated with a large number of potential complications including chronic kidney disease (CKD). Several factors have been implicated in the development of the latter, including advanced glycation end-products (AGEs), which are formed from the interaction between sugar and proteins. AGE toxicity may be triggered via different mechanisms, especially by receptor binding. Immunohistochemical studies have demonstrated the presence of AGEs in all renal structures (vessels, glomeruli, tubules and the interstitium). They appear to be involved in the exacerbation of renal injury observed during diabetic nephropathy. At present, no specific treatment is yet available, although several therapeutic approaches are under development.

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