title: High glucose down-regulates microRNA-181a-5p to increase pro-fibrotic gene expression by targeting early growth response factor 1 in HK-2 cells.
abstract: Tubulointerstitial fibrosis (TIF) plays an important role in the progression of renal fibrosis in diabetic nephropathy (DN). Accumulating evidence supports a crucial effect of early growth response factor 1 (Egr1) on renal fibrosis in DN, but the underlying mechanisms are not entirely clear. Here, we explored the aggravating role of Egr1 and identified microRNA-181a-5p (miR-181a-5p) as an upstream regulator of Egr1 in TIF of DN. We demonstrated that overexpression of Egr1 enhanced, whereas small interfering RNA targeting Egr1 decreased the expressions of transforming growth factor β1 (TGF-β1) and fibrosis-related genes including fibronectin and collagen I in human proximal tubule cell line (HK-2) cells. We then found that miR-181a-5p expression was down-regulated, accompanied by the corresponding up-regulation of Egr1, TGF-β1, fibronectin and collagen I in renal tissues of type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty rats with DN, and that the expression of miR-181a-5p was negatively correlated with the level of Egr1 in HK-2 cells treated with high glucose. Furthermore, we identified that miR-181a-5p directly suppressed Egr1 to decrease the expressions of TGF-β1, fibronectin and collagen I in HK-2 cells through targeting the 3' untranslated region of Egr1. The functional relevance of miR-181a-5p-induced Egr1 decrease was supported by inhibition and overexpression of miR-181a-5p in HK-2 cells. Thus, we concluded that aberrant Egr1 expression, which can be suppressed by miR-181a-5p directly, plays a crucial role in the progression of renal TIF in DN. This study indicates that targeting miR-181a-5p may be a novel therapeutic approach of DN.
authors.affiliation: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Endocrinology and Metabolism, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China. Electronic address: dudu20101202@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Mei-Ping
authors.initials: MP
authors.lastname: Guan
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China.
authors.forename: Jian-Gang
authors.initials: JG
authors.lastname: Bi
authors.affiliation: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Zong-Ji
authors.initials: ZJ
authors.lastname: Zheng
authors.affiliation: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: xymbright@126.com.
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Xue
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020334:Rats, Inbred OLETF; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D051766:Early Growth Response Protein 1; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D005947:Glucose
keywords: Diabetic nephropathy; Early growth response factor 1; HK-2 cell; MicroRNA-181a-5p; Renal tubulointerstitial fibrosis