Epigenetic modification of miR-10a regulates renal damage by targeting CREB1 in type 2 diabetes mellitus.
Emerging evidence has shown that microRNA-mediated gene expression modulation plays a crucial role in the pathogenesis of type 2 diabetes mellitus, but the novel miRNAs involved in type 2 diabetes and its functional regulatory mechanisms still need to be determined. In this study, we assessed the role of miR-10a in extracellular matrix accumulation in the kidney of diabetic mellitus induced by combining administration of chronic high fat diet (HFD) and low dosage of streptozotocin (STZ, 35mg/kg). Here, we found that HFD/STZ administration decreased the level of microRNA (miR-10a) expression in ICR strain mice. Overexpression of miR-10a alleviated the increased ratio of urine albumin-to-creatinine (ACR) ratio of HFD/STZ mice. In contrast, knockdown of miR-10a increased the ratio of kidney ACR in naïve mice. Furthermore, cAMP response element binding protein 1 (CREB1) was validated as a target of miR-10a in vitro and in vivo. CREB1 and its downstream fibronectin (FN, extracellular matrix) were increased in HFD/STZ-treated mice, which was reversed by kidney miR-10a overexpression. The content of CREB1 and FN was increased by miR-10a knockdown in kidney of naïve mice. Furthermore, histone deacetylase 3 (HDAC3) was revealed to be increased in kidney of HFD/STZ mice, accompanied with the augmentation of ACR ratio and FN level. Knockdown of HDAC3 with siRNA significantly caused the increase of miR-10a, resulting in the decrease in CREB1 and FN expression in kidney of HFD/STZ mice. Contrarily, HDAC3 overexpression mediated by lentivirus decreased miR-10a content, and enhanced ACR value, CREB1 and FN formation in naïve mice. Collectively, these results elucidate that HDAC3/miR-10a/CREB1 serves as a new mechanism underlying kidney injury, providing potential therapeutic targets in type 2 diabetes.
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: shanp@jsnu.edu.cn.
Qun
Q
Shan
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: ghzhengsd@jsnu.edu.cn.
Guihong
G
Zheng
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: ahzhu@jsnu.edu.cn.
Aihua
A
Zhu
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: 948113717@qq.com.
Li
L
Cao
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: lu-jun75@163.com.
Jun
J
Lu
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: wdm8610@jsnu.edu.cn.
Dongmei
D
Wu
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: zhangzifengsuper@jsnu.edu.cn.
ZiFeng
Z
Zhang
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: fshfly@126.com.
Shaohua
S
Fan
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: 306484866@qq.com.
Chunhui
C
Sun
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: hubin@jsnu.edu.cn.
Bin
B
Hu
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: ylzheng@jsnu.edu.cn.
Yuanlin
Y
Zheng
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D044127:Epigenesis, Genetic; D005353:Fibronectins / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D017362:Cyclic AMP Response Element-Binding Protein; D005353:Fibronectins; D006655:Histone Deacetylases; D035683:MicroRNAs; D000099186:Histone Deacetylase 3; C492004:Creb1 protein, mouse; C569259:MIRN10 microRNA, mouse
CREB1; HDAC3; Kidney damage; Type 2 diabetes; miR-10a