Diabetes, Metabolic Syndrome and Obesity (Apr 2020)
Egr1 Knockdown Combined with an ACE Inhibitor Ameliorates Diabetic Kidney Disease in Mice: Blockade of Compensatory Renin Increase
Abstract
Fang Hu,1 Rui Xue,2 Xiaohong Wei,1 Zheng Wang,1 Shunkui Luo,1 Jianghong Lin,1 Zhixiang Yan,3 Liao Sun1 1Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital Sun, Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Cardio-Thoracic Surgery, Zhuhai Hospital of Integrated Traditional Chinese Western Medicine, NanFang Medical University, Zhuhai, Guangdong, People’s Republic of China; 3Key Laboratory of Biomedical Imaging of Guangdong Province, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of ChinaCorrespondence: Zhixiang YanKey Laboratory of Biomedical Imaging of Guangdong Province, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of ChinaTel +86 13680373940Fax +86 7562528741Email [email protected] SunDepartment of Endocrinology and Metabolism, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of ChinaTel/Fax +86 7562528741 Email [email protected]: Increased compensatory intrarenal renin diminishes the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in the treatment of diabetic kidney disease (DKD). Early growth response-1 (Egr1) is a crucial transcriptional factor in the progress of DKD and is a potential transcription factor of intrarenal renin according to bioinformatic analysis. However, whether inhibition of Egr1 can suppress compensatory renin increase in DKD is unclear.Methods: We generated a high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mouse model. The mice were treated with either enalapril (an ACEI) or enalapril combined with a shEgr1 plasmid, and age-matched DKD mice were used as controls. Urine microalbumin, urinary renin and kidney TGF-β 1 were determined by enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) and Masson staining were used to determine renal pathological changes. Egr1, renin, TNF-α, and FN were measured by real-time quantitative PCR, Western blot, and immunohistochemistry. The SV40-MES13 murine mesangial cell line was transfected with pENTER-Egr1 plasmid and siEgr1.Results: Our results showed that enalapril increased the renin level of urinary and renal in DKD mice, while shEgr1 attenuated this effect. In addition, enalapril treatment reduced the levels of urinary microalbumin, TNF-α, TGF-β 1 and FN, and alleviated the pathological changes, while shEgr1 strengthened these effects. The protein and mRNA expression of renin in the SV40 MES13 cells was upregulated and downregulated following overexpression and silence of Egr1, respectively.Conclusion: Silence of Egr1 could alleviate renal injury in DKD by downregulating intrarenal renin.Keywords: diabetic kidney disease, early growth response-1, renin-angiotensin system
