title: MicroRNA-23b Targets Ras GTPase-Activating Protein SH3 Domain-Binding Protein 2 to Alleviate Fibrosis and Albuminuria in Diabetic Nephropathy.
abstract: Diabetic nephropathy (DN) is a frequent and severe complication of diabetes that is structurally characterized by glomerular basement membrane thickening, extracellular matrix accumulation, and destabilization of podocyte foot processes. MicroRNAs (miRNAs) are dysregulated in DN, but identification of the specific miRs involved remains incomplete. Here, we confirm that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of miR-23b compared with those of their nondiabetic counterparts. Furthermore, exposure to high glucose downregulated miR-23b in cultured kidney cells. In contrast, renal expression of Ras GTPase-activating protein SH3 domain-binding protein 2 (G3BP2), a putative miR-23b target, increased in DN. In vitro, overexpression of miR-23b decreased, and inhibition of miR-23b increased, G3BP2 expression levels. Bioinformatics analysis also revealed p53 binding sites in the miR-23b promoter; in vitro inhibition of p53 or the upstream p38 mitogen-activated protein kinase (p38MAPK) upregulated miR-23b expression in high-glucose conditions. In turn, inhibition of G3BP2 or overexpression of miR-23b downregulated p53 and p38MAPK expression in high-glucose conditions. In vivo, overexpression of miR-23b or inhibition of p53 in db/db mice reversed hyperalbuminuria and kidney fibrosis, whereas miR-23b antagomir treatment promoted renal fibrosis and increased albuminuria in wild-type mice. These data suggest that hyperglycemia regulates pathogenic processes in DN through an miR-23b/G3BP2 feedback circuit involving p38MAPK and p53. In conclusion, these results reveal a role for miR-23b in DN and indicate a novel potential therapeutic target.
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: Binghai
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Li
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: Jieting
authors.initials: J
authors.lastname: Liu
authors.affiliation: Clinical Laboratory of Hong Qi Hospital, Mudanjiang Medical University, Heilongjiang, People's Republic of China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Han
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: He
authors.initials: H
authors.lastname: Bai
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Clinical Laboratory of Hong Qi Hospital, Mudanjiang Medical University, Heilongjiang, People's Republic of China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and.
authors.forename: Hongchuang
authors.initials: H
authors.lastname: Ma
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and yanhui_chu@163.com mdjmujin@163.com.
authors.forename: Xiudong
authors.initials: X
authors.lastname: Jin
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Medical Research Center, and yanhui_chu@163.com mdjmujin@163.com.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Chu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000419:Albuminuria / Q000150:complications / Q000201:enzymology*; D000818:Animals; D003928:Diabetic Nephropathies / Q000150:complications / Q000201:enzymology*; D005355:Fibrosis / Q000150:complications / Q000201:enzymology; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D016601:RNA-Binding Proteins; D020703:ras GTPase-Activating Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C576524:G3BP2 protein, mouse; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; D016601:RNA-Binding Proteins; D020703:ras GTPase-Activating Proteins
keywords: chronic kidney disease; diabetes; diabetic nephropathy
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