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Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway

Macrophage infiltration has been linked to the pathogenesis of diabetic nephropathy (DN). However, how infiltrating macrophages affect the progression of DN is unknown. Although infiltrating macrophages produce pro-inflammatory mediators and induce apoptosis in a variety of target cells, there are n...

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Autores principales: Guo, Yinfeng, Song, Zhixia, Zhou, Min, Yang, Ying, Zhao, Yu, Liu, Bicheng, Zhang, Xiaoliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581109/
https://www.ncbi.nlm.nih.gov/pubmed/28881810
http://dx.doi.org/10.18632/oncotarget.18394
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author Guo, Yinfeng
Song, Zhixia
Zhou, Min
Yang, Ying
Zhao, Yu
Liu, Bicheng
Zhang, Xiaoliang
author_facet Guo, Yinfeng
Song, Zhixia
Zhou, Min
Yang, Ying
Zhao, Yu
Liu, Bicheng
Zhang, Xiaoliang
author_sort Guo, Yinfeng
collection PubMed
description Macrophage infiltration has been linked to the pathogenesis of diabetic nephropathy (DN). However, how infiltrating macrophages affect the progression of DN is unknown. Although infiltrating macrophages produce pro-inflammatory mediators and induce apoptosis in a variety of target cells, there are no studies in podocytes. Therefore, we tested the contribution of macrophages to podocytes apoptosis in DN. in vivo experiments showed that apoptosis in podocytes was increased in streptozocin (STZ)-induced diabetic rats compared with control rats and that this apoptosis was accompanied by increased macrophages infiltration in the kidney. Then, we established a co-culture system to study the interaction between macrophages and podocytes in the absence or presence of high glucose. Macrophages did not trigger podocytes apoptosis when they were co-cultured in the absence of high glucose in a transwell co-culture system. Additionally, although podocyte apoptosis was increased after high glucose stimulation, there was a further enhancement of podocyte apoptosis when podocytes were co-cultured with macrophages in the presence of high glucose compared with podocytes cultured alone in high glucose. Mechanistically, we found that macrophages were activated when they were exposed to high glucose, displaying pro-inflammatory M1 polarization. Furthermore, conditioned media (CM) from such high glucose-activated M1 macrophages (HG-CM) trigged podocytes apoptosis in a reactive oxygen species (ROS)-p38mitogen-activated protein kinases (p38MAPK) dependent manner, which was abolished by either a ROS inhibitor (Tempo) or a p38MAPK inhibitor (SB203580). Finally, we identified tumor necrosis factor (TNF-α) as a key mediator of high glucose-activated macrophages to induce podocytes apoptosis because an anti-TNF-α neutralizing antibody blunted the apoptotic response, excess ROS generation and p38MPAK activation in podocytes induced by HG-CM. Moreover, addition of recombinant TNF-α similarly resulted in podocytes apoptosis. In summary, the TNF-α that was released by high glucose-activated macrophages promoted podocytes apoptosis via ROS-p38MAPK pathway. Blockade of TNF-α secretion from high glucose activated macrophages and ROS-p38MAPK pathway might be effective therapeutic options to limit podocytes apoptosis and delay the progression of diabetic nephropathy.
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spelling pubmed-55811092017-09-06 Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway Guo, Yinfeng Song, Zhixia Zhou, Min Yang, Ying Zhao, Yu Liu, Bicheng Zhang, Xiaoliang Oncotarget Research Paper Macrophage infiltration has been linked to the pathogenesis of diabetic nephropathy (DN). However, how infiltrating macrophages affect the progression of DN is unknown. Although infiltrating macrophages produce pro-inflammatory mediators and induce apoptosis in a variety of target cells, there are no studies in podocytes. Therefore, we tested the contribution of macrophages to podocytes apoptosis in DN. in vivo experiments showed that apoptosis in podocytes was increased in streptozocin (STZ)-induced diabetic rats compared with control rats and that this apoptosis was accompanied by increased macrophages infiltration in the kidney. Then, we established a co-culture system to study the interaction between macrophages and podocytes in the absence or presence of high glucose. Macrophages did not trigger podocytes apoptosis when they were co-cultured in the absence of high glucose in a transwell co-culture system. Additionally, although podocyte apoptosis was increased after high glucose stimulation, there was a further enhancement of podocyte apoptosis when podocytes were co-cultured with macrophages in the presence of high glucose compared with podocytes cultured alone in high glucose. Mechanistically, we found that macrophages were activated when they were exposed to high glucose, displaying pro-inflammatory M1 polarization. Furthermore, conditioned media (CM) from such high glucose-activated M1 macrophages (HG-CM) trigged podocytes apoptosis in a reactive oxygen species (ROS)-p38mitogen-activated protein kinases (p38MAPK) dependent manner, which was abolished by either a ROS inhibitor (Tempo) or a p38MAPK inhibitor (SB203580). Finally, we identified tumor necrosis factor (TNF-α) as a key mediator of high glucose-activated macrophages to induce podocytes apoptosis because an anti-TNF-α neutralizing antibody blunted the apoptotic response, excess ROS generation and p38MPAK activation in podocytes induced by HG-CM. Moreover, addition of recombinant TNF-α similarly resulted in podocytes apoptosis. In summary, the TNF-α that was released by high glucose-activated macrophages promoted podocytes apoptosis via ROS-p38MAPK pathway. Blockade of TNF-α secretion from high glucose activated macrophages and ROS-p38MAPK pathway might be effective therapeutic options to limit podocytes apoptosis and delay the progression of diabetic nephropathy. Impact Journals LLC 2017-06-07 /pmc/articles/PMC5581109/ /pubmed/28881810 http://dx.doi.org/10.18632/oncotarget.18394 Text en Copyright: © 2017 Guo et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Guo, Yinfeng
Song, Zhixia
Zhou, Min
Yang, Ying
Zhao, Yu
Liu, Bicheng
Zhang, Xiaoliang
Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway
title Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway
title_full Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway
title_fullStr Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway
title_full_unstemmed Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway
title_short Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway
title_sort infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via tnf-α-ros-p38mapk pathway
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581109/
https://www.ncbi.nlm.nih.gov/pubmed/28881810
http://dx.doi.org/10.18632/oncotarget.18394
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