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Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response

The pathogenesis of diabetic kidney disease (DKD) is complicated. Current clinical treatments fail to achieve satisfactory efficacy in the prevention of DKD progression, it urgently needs novel and effective treatment for DKD. In this study, we firstly demonstrated that renal lipid metabolism abnorm...

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Autores principales: Cao, Zhonglian, Zhao, Hui, Fan, Jiajun, Shen, Yilan, Han, Lei, Jing, Guangjun, Zeng, Xian, Jin, Xin, Zhu, Zeguo, Bian, Qi, Nan, Yanyang, Hu, Xiaozhi, Mei, Xiaobin, Ju, Dianwen, Yang, Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9842640/
https://www.ncbi.nlm.nih.gov/pubmed/36646672
http://dx.doi.org/10.1038/s41420-023-01304-5
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author Cao, Zhonglian
Zhao, Hui
Fan, Jiajun
Shen, Yilan
Han, Lei
Jing, Guangjun
Zeng, Xian
Jin, Xin
Zhu, Zeguo
Bian, Qi
Nan, Yanyang
Hu, Xiaozhi
Mei, Xiaobin
Ju, Dianwen
Yang, Ping
author_facet Cao, Zhonglian
Zhao, Hui
Fan, Jiajun
Shen, Yilan
Han, Lei
Jing, Guangjun
Zeng, Xian
Jin, Xin
Zhu, Zeguo
Bian, Qi
Nan, Yanyang
Hu, Xiaozhi
Mei, Xiaobin
Ju, Dianwen
Yang, Ping
author_sort Cao, Zhonglian
collection PubMed
description The pathogenesis of diabetic kidney disease (DKD) is complicated. Current clinical treatments fail to achieve satisfactory efficacy in the prevention of DKD progression, it urgently needs novel and effective treatment for DKD. In this study, we firstly demonstrated that renal lipid metabolism abnormality and inflammation significantly changed in DKD conditions by mining public transcriptomic data of DKD patient samples. KEGG analysis further exhibited the critical role of vascular endothelial growth factor B (VEGF-B) and interleukin 17A (IL-17A) signal pathways in DKD progression, indicating that VEGF-B and IL-17A might be the promising targets for DKD treatment. Then the potential of a novel combination therapy, anti-VEGF-B plus anti-IL-17A antibody, was evaluated for DKD treatment. Our results demonstrated that simultaneous blockade of VEGF-B and IL-17A signaling with their neutralizing antibodies alleviated renal damage and ameliorated renal function. The therapeutic effectiveness was not only related to the reduced lipid deposition especially the neutral lipids in kidney but also associated with the decreased inflammation response. Moreover, the therapy alleviated renal fibrosis by reducing collagen deposition and the expression of fibronectin and α-SMA in kidney tissues. RNA-seq analysis indicated that differential expression genes (DEGs) in db/db mice were significantly clustered into lipid metabolism, inflammation, fibrosis and DKD pathology-related pathways, and 181 of those DEGs were significantly reversed by the combinatory treatment, suggesting the underlying mechanism of administration of anti-VEGF-B and anti-IL-17A antibodies in DKD treatment. Taken together, this study identified that renal lipid metabolism abnormality and inflammation were critically involved in the progression of DKD, and simultaneous blockade of VEGF-B and IL-17A signaling represents a potential DKD therapeutic strategy.
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spelling pubmed-98426402023-01-18 Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response Cao, Zhonglian Zhao, Hui Fan, Jiajun Shen, Yilan Han, Lei Jing, Guangjun Zeng, Xian Jin, Xin Zhu, Zeguo Bian, Qi Nan, Yanyang Hu, Xiaozhi Mei, Xiaobin Ju, Dianwen Yang, Ping Cell Death Discov Article The pathogenesis of diabetic kidney disease (DKD) is complicated. Current clinical treatments fail to achieve satisfactory efficacy in the prevention of DKD progression, it urgently needs novel and effective treatment for DKD. In this study, we firstly demonstrated that renal lipid metabolism abnormality and inflammation significantly changed in DKD conditions by mining public transcriptomic data of DKD patient samples. KEGG analysis further exhibited the critical role of vascular endothelial growth factor B (VEGF-B) and interleukin 17A (IL-17A) signal pathways in DKD progression, indicating that VEGF-B and IL-17A might be the promising targets for DKD treatment. Then the potential of a novel combination therapy, anti-VEGF-B plus anti-IL-17A antibody, was evaluated for DKD treatment. Our results demonstrated that simultaneous blockade of VEGF-B and IL-17A signaling with their neutralizing antibodies alleviated renal damage and ameliorated renal function. The therapeutic effectiveness was not only related to the reduced lipid deposition especially the neutral lipids in kidney but also associated with the decreased inflammation response. Moreover, the therapy alleviated renal fibrosis by reducing collagen deposition and the expression of fibronectin and α-SMA in kidney tissues. RNA-seq analysis indicated that differential expression genes (DEGs) in db/db mice were significantly clustered into lipid metabolism, inflammation, fibrosis and DKD pathology-related pathways, and 181 of those DEGs were significantly reversed by the combinatory treatment, suggesting the underlying mechanism of administration of anti-VEGF-B and anti-IL-17A antibodies in DKD treatment. Taken together, this study identified that renal lipid metabolism abnormality and inflammation were critically involved in the progression of DKD, and simultaneous blockade of VEGF-B and IL-17A signaling represents a potential DKD therapeutic strategy. Nature Publishing Group UK 2023-01-16 /pmc/articles/PMC9842640/ /pubmed/36646672 http://dx.doi.org/10.1038/s41420-023-01304-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cao, Zhonglian
Zhao, Hui
Fan, Jiajun
Shen, Yilan
Han, Lei
Jing, Guangjun
Zeng, Xian
Jin, Xin
Zhu, Zeguo
Bian, Qi
Nan, Yanyang
Hu, Xiaozhi
Mei, Xiaobin
Ju, Dianwen
Yang, Ping
Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response
title Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response
title_full Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response
title_fullStr Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response
title_full_unstemmed Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response
title_short Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response
title_sort simultaneous blockade of vegf-b and il-17a ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9842640/
https://www.ncbi.nlm.nih.gov/pubmed/36646672
http://dx.doi.org/10.1038/s41420-023-01304-5
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