title: Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy.
abstract: Recently, our group has developed a therapeutic hypertensive vaccine against angiotensin (Ang) II type 1 receptor (AT1R) named ATRQβ-001. To explore its potential effectiveness on streptozotocin-induced diabetic nephropathy, male Sprague Dawley rats were randomly divided into two groups: a control and a diabetic model. After 1 week, the diabetic rats were divided into four subgroups (each with 15 rats) for 14-week treatments with saline, olmesartan, ATRQβ-001, and Qβ virus-like particle (VLP), respectively. In addition to lower blood pressure, ATRQβ-001 vaccination ameliorated biochemical parameter changes of renal dysfunction, mesangial expansion, and fibrosis through inhibiting oxidative stress, macrophage infiltration, and proinflammatory factor expression. Furthermore, ATRQβ-001 vaccination suppressed renal Ang II-AT1R activation and abrogated the downregulation of angiotensin-converting enzyme 2-Ang (1-7), similar to olmesartan treatment, while no obvious feedback activation of circulating or local renin-angiotensin system (RAS) was only observed in vaccine group. In rat mesangial cells, the anti-ATR-001 antibody inhibited high glucose-induced transforming growth factor-β1 (TGF)-β1/Smad3 signal pathway. Additionally, no significant immune-mediated damage was detected in vaccinated animals. In conclusion, the ATRQβ-001 vaccine ameliorated streptozotocin-induced diabetic renal injury via modulating two RAS axes and inhibiting TGF-β1/Smad3 signal pathway, providing a novel, safe, and promising method to treat diabetic nephropathy.
  
  
  CONCLUSIONS
  Overactivation of RAS plays a crucial role in the development of the DN. Our aim was to verify the effectiveness of ATRQβ-001 vaccine in STZ-induced DN. The ATRQβ-001 modulated two RAS axes and inhibited TGF-β1/Smad3 signal pathway. The vaccine therapy may provide a novel, safe, and promising method to treat DN.
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ding
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Du
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Yan
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Chen
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Yanzhao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Xiajun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Yihuan
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Shijia
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Liangping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Hongrong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Hailang
authors.initials: H
authors.lastname: Wu
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Yu
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Zihua
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China. skycreeper@126.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
mesh_terms: D000804:Angiotensin II / Q000097:blood; D000818:Animals; D015415:Biomarkers; D001774:Blood Chemical Analysis; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005355:Fibrosis; D007677:Kidney Function Tests; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D050199:Podocytes / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*; D012083:Renin / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D013311:Streptozocin / Q000009:adverse effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D014612:Vaccines; D000804:Angiotensin II; D013311:Streptozocin; D012083:Renin
keywords: Angiotensin receptor; Diabetic nephropathy; Renin-angiotensin system; Streptozotocin; Vaccine