Emodin ameliorates renal injury and fibrosis via regulating the miR-490-3p/HMGA2 axis

Renal fibrosis is a major pathological feature of chronic kidney disease (CKD). While emodin is reported to elicit anti-fibrotic effects on renal injury, little is known about its effects on microRNA (miRNA)-modulated mechanisms in renal fibrosis. In this study, we established a unilateral ureteral obstruction (UUO) model and a transforming growth factor (TGF)-β1-induced normal rat renal tubular epithelial cell line (NRK-52E) model to investigate the protective effects of emodin on renal fibrosis and its miRNA/target gene mechanisms. Dual-luciferase assay was performed to confirm the direct binding of miRNA and target genes in HEK293 cells. Results showed that oral administration of emodin significantly ameliorated the loss of body weight and the increase in physicochemical parameters, including serum uric acid, creatinine, and urea nitrogen in UUO mice. Inflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin (IL)-1β, but not IL-6, were down-regulated by emodin administration. Emodin decreased the expression levels of TGF-β1 and fibrotic-related proteins, including alpha-smooth muscle actin, Collagen IV, and Fibronectin, and increased the expression of E-cadherin. Furthermore, miR-490-3p was decreased in UUO mice and negatively correlated with increased expression of high migration protein A2 (HMGA2). We further confirmed HMGA2 was the target of miR-490-3p. Transfection of miR-490-3p mimics decreased, while transfection of miR-490-3p inhibitors increased fibrotic-related proteins and HMGA2 expression levels in TGF-β1-induced NRK-52E cells. Furthermore, transfection of miR-490-3p mimics enhanced the anti-fibrotic effects of emodin, while transfection of miR-490-3p inhibitors abolished the protective effects of emodin. Thus, as a novel target of emodin that prevents renal fibrosis in the HMGA2-dependent signaling pathway, miR-490-3p has potential implications in CKD pathology.

[1]  Y. Zhang,et al.  Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice , 2022, Signal Transduction and Targeted Therapy.

[2]  Cheng Ye,et al.  Stewed Rhubarb Decoction Ameliorates Adenine-Induced Chronic Renal Failure in Mice by Regulating Gut Microbiota Dysbiosis , 2022, Frontiers in Pharmacology.

[3]  Liang Ma,et al.  Natural Flavonoid Pectolinarigenin Alleviated Hyperuricemic Nephropathy via Suppressing TGFβ/SMAD3 and JAK2/STAT3 Signaling Pathways , 2022, Frontiers in Pharmacology.

[4]  L. Trombetta,et al.  Chrysin Ameliorates Cyclosporine-A-Induced Renal Fibrosis by Inhibiting TGF-β1-Induced Epithelial–Mesenchymal Transition , 2021, International journal of molecular sciences.

[5]  Dongmei Li,et al.  Emodin-induced autophagic cell death hinders epithelial-mesenchymal transition via regulation of BMP-7/TGF-β1 in renal fibrosis. , 2021, Journal of pharmacological sciences.

[6]  Xiaohong Wang,et al.  Angiotensin IV attenuates diabetic cardiomyopathy via suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis , 2021, Theranostics.

[7]  K. Kalantar-Zadeh,et al.  Chronic kidney disease , 2021, The Lancet.

[8]  Mengkui Sun,et al.  MicroRNA-302b mitigates renal fibrosis via inhibiting TGF-β/Smad pathway activation , 2021, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[9]  Yi Liu,et al.  Long noncoding RNA-SNHG20 promotes silica-induced pulmonary fibrosis by miR-490-3p/TGFBR1 axis. , 2021, Toxicology.

[10]  R. Kulshreshtha,et al.  miR‐490: A potential biomarker and therapeutic target in cancer and other diseases , 2020, Journal of cellular physiology.

[11]  Jinpeng Li,et al.  Emodin Retarded Renal Fibrosis Through Regulating HGF and TGFβ–Smad Signaling Pathway , 2020, Drug design, development and therapy.

[12]  M. Czubryt,et al.  Targeting the Renin-Angiotensin-Aldosterone System in Fibrosis. , 2020, Matrix biology : journal of the International Society for Matrix Biology.

[13]  Z. Ai,et al.  Deciphering the Pharmacological Mechanisms of Taohe-Chengqi Decoction Extract Against Renal Fibrosis Through Integrating Network Pharmacology and Experimental Validation In Vitro and In Vivo , 2020, Frontiers in Pharmacology.

[14]  P. Komenda,et al.  Screening for chronic kidney disease: moving toward more sustainable health care. , 2020, Current opinion in nephrology and hypertension.

[15]  Wei Shi,et al.  Hirudin improves renal interstitial fibrosis by reducing renal tubule injury and inflammation in unilateral ureteral obstruction (UUO) mice. , 2020, International immunopharmacology.

[16]  L. G. Vu,et al.  Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 , 2020, The Lancet.

[17]  Xiuxia Liu,et al.  Emodin relieved lipopolysaccharide‐evoked inflammatory damage in WI‐38 cells by up‐regulating taurine up‐regulated gene 1 , 2020, BioFactors.

[18]  Bo Zhang,et al.  Curcumin attenuates renal interstitial fibrosis of obstructive nephropathy by suppressing epithelial-mesenchymal transition through inhibition of the TLR4/NF-кB and PI3K/AKT signalling pathways , 2020, Pharmaceutical biology.

[19]  Hong Zheng,et al.  Emerging role of miRNAs in renal fibrosis , 2020, RNA biology.

[20]  Han Liu,et al.  Emodin Attenuates Severe Acute Pancreatitis via Antioxidant and Anti-inflammatory Activity , 2019, Inflammation.

[21]  Jingyi Sun,et al.  Emodin relieves hypoxia-triggered injury via elevation of microRNA-25 in PC-12 cells , 2019, Artificial cells, nanomedicine, and biotechnology.

[22]  Fang Zhang,et al.  miR-490-3p functions as a tumor suppressor in glioma by inhibiting high-mobility group AT-hook 2 expression , 2019, Experimental and therapeutic medicine.

[23]  Ruijin Xie,et al.  Emodin weakens liver inflammatory injury triggered by lipopolysaccharide through elevating microRNA-145 in vitro and in vivo , 2019, Artificial cells, nanomedicine, and biotechnology.

[24]  O. Akchurin,et al.  Chronic Kidney Disease and Dietary Measures to Improve Outcomes. , 2019, Pediatric clinics of North America.

[25]  F. Tacke,et al.  Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. , 2019, Molecular aspects of medicine.

[26]  P. Boor,et al.  Cellular and molecular mechanisms of kidney fibrosis. , 2019, Molecular aspects of medicine.

[27]  Taotao Ma,et al.  TGF-β/Smad and Renal Fibrosis. , 2019, Advances in experimental medicine and biology.

[28]  Baoping Chen,et al.  miR‐133b and miR‐199b knockdown attenuate TGF‐&bgr;1‐induced epithelial to mesenchymal transition and renal fibrosis by targeting SIRT1 in diabetic nephropathy , 2018, European journal of pharmacology.

[29]  G. Anton,et al.  Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome , 2018, Journal of immunology research.

[30]  A. Mokdad,et al.  Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. , 2018, Kidney international.

[31]  R. Roman,et al.  Inflammation and renal fibrosis: Recent developments on key signaling molecules as potential therapeutic targets , 2018, European journal of pharmacology.

[32]  R. Roman,et al.  Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. , 2018, Physiological genomics.

[33]  G. Deng,et al.  Emodin ameliorates renal fibrosis in rats via TGF-β1/Smad signaling pathway and function study of Smurf 2 , 2018, International Urology and Nephrology.

[34]  Hong Xiang,et al.  Emodin Alleviates Sodium Taurocholate-Induced Pancreatic Acinar Cell Injury via MicroRNA-30a-5p-Mediated Inhibition of High-Temperature Requirement A/Transforming Growth Factor Beta 1 Inflammatory Signaling , 2017, Front. Immunol..

[35]  P. Boor,et al.  Treatment of Renal Fibrosis-Turning Challenges into Opportunities. , 2017, Advances in chronic kidney disease.

[36]  Maria João Pires,et al.  Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies. , 2017, In vivo.

[37]  Q. Guo,et al.  miR‑221 targets HMGA2 to inhibit bleomycin‑induced pulmonary fibrosis by regulating TGF‑β1/Smad3-induced EMT. , 2016, International journal of molecular medicine.

[38]  R. Kalluri,et al.  Partial Epithelial-to-Mesenchymal Transition and Other New Mechanisms of Kidney Fibrosis , 2016, Trends in Endocrinology & Metabolism.

[39]  Jian Ni,et al.  Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics , 2016, Phytotherapy research : PTR.

[40]  Hong Liu,et al.  Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro by activating autophagy , 2016, Acta Pharmacologica Sinica.

[41]  F. Glowacki,et al.  Implication des microARN dans la fibrose rénale , 2015 .

[42]  Wei Liu,et al.  MicroRNA‐490‐3p regulates cell proliferation and apoptosis by targeting HMGA2 in osteosarcoma , 2015, FEBS letters.

[43]  R. Kalluri,et al.  Epithelial to Mesenchymal Transition induces cell cycle arrest and parenchymal damage in renal fibrosis , 2015, Nature Medicine.

[44]  S. Weiss,et al.  Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease , 2015, Nature Medicine.

[45]  S. Friedman,et al.  Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. , 2015, Gastroenterology.

[46]  Tao Yang,et al.  EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy. , 2015, Journal of the American Society of Nephrology : JASN.

[47]  D. Rockey,et al.  Fibrosis--A Common Pathway to Organ Injury and Failure. , 2015, The New England journal of medicine.

[48]  K. Zen,et al.  Evaluation of microRNAs miR-196a, miR-30a-5P, and miR-490 as biomarkers of disease activity among patients with FSGS. , 2014, Clinical journal of the American Society of Nephrology : CJASN.

[49]  Xiaofeng Zhu,et al.  Therapeutic Effect of Emodin on Collagen-Induced Arthritis in Mice , 2013, Inflammation.

[50]  R. Kalluri,et al.  Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. , 2013, American journal of physiology. Cell physiology.

[51]  Xiao-ming Meng,et al.  miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes , 2013, Diabetologia.

[52]  J. Yue,et al.  Rheum officinale (a traditional Chinese medicine) for chronic kidney disease. , 2012, The Cochrane database of systematic reviews.

[53]  T. Gehr,et al.  Chronic kidney disease: detection and evaluation. , 2011, American family physician.

[54]  Cheuk-Man Yu,et al.  TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. , 2011, Journal of the American Society of Nephrology : JASN.

[55]  M. Le Hir,et al.  Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? , 2011, The Journal of clinical investigation.

[56]  P. Boor,et al.  Renal fibrosis: novel insights into mechanisms and therapeutic targets , 2010, Nature Reviews Nephrology.

[57]  Xiao-ming Meng,et al.  miR-192 mediates TGF-beta/Smad3-driven renal fibrosis. , 2010, Journal of the American Society of Nephrology : JASN.

[58]  M. Iwano EMT and TGF-beta in renal fibrosis. , 2010, Frontiers in bioscience.

[59]  P. Squires,et al.  TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Therapeutic Intervention in Diabetic Nephropathy , 2009, American Journal of Nephrology.