title: NMDA receptors participate in the progression of diabetic kidney disease by decreasing Cdc42-GTP activation in podocytes.
abstract: Podocytes play important roles in the progression of diabetic kidney disease (DKD) and these roles are closely associated with cytoskeletal actin dynamics. N-Methyl-d-aspartate receptors (NMDARs), which consist of two functional NR1 subunits and two regulatory NR2 subunits, are widely expressed in the brain but are also found in podocytes. Here, we found increased NR1 expression in two diabetic mouse models and in podocytes incubated in high glucose (HG). In diabetic mice, knockdown of NR1 using lentivirus carrying NR1-shRNA ameliorated the pathological features associated with DKD, and reversed the decreased expression of synaptopodin and Wilms' tumour-1. In podocytes incubated with HG, NR1 was secreted from the endoplasmic reticulum and this was blocked by bisindolylmaleimide I. NR1 knockdown decreased the cell shape remodelling, cell collapse, bovine serum albumin permeability, and migration induced by HG. After HG incubation, levels of cell division control protein 42 (Cdc42) and its active form increased, and a significantly higher Cdc42-GTP level, increased Cdc42 translocation onto the leading edges, and lower migration ability were found in podocytes with NR1 knockdown. Increases in the number and length of filopodia were found in podocytes with NR1 knockdown but these were abolished by Cdc42-GTP blockade with ML141. In conclusion, the activation of NMDARs plays an important role in DKD by reducing Cdc42-GTP activation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. chenjianghua@zju.edu.cn.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China. chenjianghua@zju.edu.cn.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China. chenjianghua@zju.edu.cn.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China. chenjianghua@zju.edu.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Rending
authors.initials: R
authors.lastname: Wang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Zhechi
authors.initials: Z
authors.lastname: He
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Huang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Xuelin
authors.initials: X
authors.lastname: He
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yinggang
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Nephrology Department, Shaoxing People's Hospital of Zhejiang Province, Shaoxing, China.
authors.forename: Shuijuan
authors.initials: S
authors.lastname: Shen
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Shao
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Xiujin
authors.initials: X
authors.lastname: Shen
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Weng
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.|Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lin
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. jiashen@zju.edu.cn.|Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China. jiashen@zju.edu.cn.|Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China. jiashen@zju.edu.cn.|Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China. jiashen@zju.edu.cn.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D020764:cdc42 GTP-Binding Protein; D005947:Glucose
keywords: Cdc42; NMDA receptor; diabetic kidney disease; podocyte