title: CXCL8 Antagonist Improves Diabetic Nephropathy in Male Mice With Diabetes and Attenuates High Glucose-Induced Mesangial Injury.
abstract: Inflammation is recognized as a crucial contribution to diabetic nephropathy (DN). CXCL8 binds to its CXC chemokine receptors (CXCR1 and CXCR2) for recruiting neutrophil infiltration and initiates tissue inflammation. Therefore, we explored the effect of CXCR1 and CXCR2 inhibition on DN. This was achieved by CXCL8(3-72)K11R/G31P (G31P), an antagonist of CXCL8 that has exhibited therapeutic efficacy in inflammatory diseases and malignancies. In this study, we found that renal leukocyte accumulation and rapid increases of CXCL8 occurred in high-fat diet/streptozocin-induced diabetic mice. G31P effectively reduced urine volume, urine albumin/creatinine ratio, blood urea nitrogen, and creatinine clearance rate in mice with diabetes. In addition, renal histopathologic changes including mesangial expansion, glomerulosclerosis, and extracellular matrix deposition were partially moderated in G31P-treated diabetic mice. Furthermore, G31P attenuated renal inflammation and renal fibrosis of diabetic mice by inhibiting proinflammatory and profibrotic elements. G31P also inhibited high glucose-induced inflammatory and fibrotic factor upregulation in human renal mesangial cells. At the molecular level, G31P inhibited activation of CXCR1/2 downstream signaling JAK2/STAT3 and ERK1/2 pathways in in vitro and in vivo experiments. Our results suggest blockade of CXCR1/2 by G31P could confer renoprotective effects that offer potential therapeutic opportunities in DN.
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian 116011, Liaoning, China.|Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian 116011, Liaoning, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China.
authors.forename: Jianling
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian 116011, Liaoning, China.
authors.forename: Muhammad Noman
authors.initials: MN
authors.lastname: Khan
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian 116011, Liaoning, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian 116011, Liaoning, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, 999079 Hsinchu, Taiwan.
authors.forename: Jya-Wei
authors.initials: JW
authors.lastname: Cheng
authors.affiliation: Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Gordon
authors.affiliation: College of Biology Science, China Agricultural University, Beijing 100000, China.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian 116011, Liaoning, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000633:toxicity*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D013311:Streptozocin
chemical_list: C000604253:CXCL8(3-72)K11R,G31P, human; D007004:Hypoglycemic Agents; D016209:Interleukin-8; D010446:Peptide Fragments; D013311:Streptozocin; D005947:Glucose