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Article: Amelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells Via Hepatocyte Growth Factor/c‐Met Signaling in Obesity‐Associated Kidney Injury

TitleAmelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells Via Hepatocyte Growth Factor/c‐Met Signaling in Obesity‐Associated Kidney Injury
Authors
KeywordsEndoplasmic reticulum stress
Hepatocyte growth factor
Induced pluripotent stem cells
Lipotoxicity
Mesenchymal stem cells
Issue Date2019
PublisherWiley, published in association with AlphaMed Press. The Journal's web site is located at http://stemcellsjournals.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2157-6580/
Citation
Stem Cells Translational Medicine, 2019 How to Cite?
AbstractRecent advances in the understanding of lipid metabolism suggest a critical role of endoplasmic reticulum (ER) stress in obesity‐induced kidney injury. Hepatocyte growth factor (HGF) is a pleiotropic cytokine frequently featured in stem cell therapy with distinct renotropic benefits. This study aims to define the potential link between human induced pluripotent stem cell‐derived mesenchymal stem cells (iPS‐MSCs)/bone marrow‐derived MSCs (BM‐MSCs) and ER stress in lipotoxic kidney injury induced by palmitic acid (PA) in renal tubular cells and by high‐fat diet (HFD) in mice. iPS‐MSCs or BM‐MSCs alleviated ER stress (by preventing induction of Bip, chop, and unfolded protein response), inflammation (Il6, Cxcl1, and Cxcl2), and apoptosis (Bax/Bcl2 and terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling‐positive cells) in renal cortex of animals exposed to HFD thus mitigating histologic damage and albuminuria, via activating HGF/c‐Met paracrine signaling that resulted in enhanced HGF secretion in the glomerular compartment and c‐Met expression in the tubules. Coculture experiments identified glomerular endothelial cells (GECs) to be the exclusive source of glomerular HGF when incubated with either iPS‐MSCs or BM‐MSCs in the presence of PA. Furthermore, both GEC‐derived HGF and exogenous recombinant HGF attenuated PA‐induced ER stress in cultured tubular cells, and this effect was abrogated by a neutralizing anti‐HGF antibody. Taken together, this study is the first to demonstrate that MSCs ameliorate lipotoxic kidney injury via a novel microenvironment‐dependent paracrine HGF/c‐Met signaling mechanism to suppress ER stress and its downstream pro‐inflammatory and pro‐apoptotic consequences.
Persistent Identifierhttp://hdl.handle.net/10722/272281
ISSN
2017 Impact Factor: 4.929
2015 SCImago Journal Rankings: 2.049

 

DC FieldValueLanguage
dc.contributor.authorLi, B-
dc.contributor.authorLeung, JCK-
dc.contributor.authorChan, LYY-
dc.contributor.authorYiu, WH-
dc.contributor.authorLi, Y-
dc.contributor.authorLok, SWY-
dc.contributor.authorLiu, WH-
dc.contributor.authorChan, KW-
dc.contributor.authorTse, HF-
dc.contributor.authorLai, KN-
dc.contributor.authorTang, SCW-
dc.date.accessioned2019-07-20T10:39:12Z-
dc.date.available2019-07-20T10:39:12Z-
dc.date.issued2019-
dc.identifier.citationStem Cells Translational Medicine, 2019-
dc.identifier.issn2157-6564-
dc.identifier.urihttp://hdl.handle.net/10722/272281-
dc.description.abstractRecent advances in the understanding of lipid metabolism suggest a critical role of endoplasmic reticulum (ER) stress in obesity‐induced kidney injury. Hepatocyte growth factor (HGF) is a pleiotropic cytokine frequently featured in stem cell therapy with distinct renotropic benefits. This study aims to define the potential link between human induced pluripotent stem cell‐derived mesenchymal stem cells (iPS‐MSCs)/bone marrow‐derived MSCs (BM‐MSCs) and ER stress in lipotoxic kidney injury induced by palmitic acid (PA) in renal tubular cells and by high‐fat diet (HFD) in mice. iPS‐MSCs or BM‐MSCs alleviated ER stress (by preventing induction of Bip, chop, and unfolded protein response), inflammation (Il6, Cxcl1, and Cxcl2), and apoptosis (Bax/Bcl2 and terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling‐positive cells) in renal cortex of animals exposed to HFD thus mitigating histologic damage and albuminuria, via activating HGF/c‐Met paracrine signaling that resulted in enhanced HGF secretion in the glomerular compartment and c‐Met expression in the tubules. Coculture experiments identified glomerular endothelial cells (GECs) to be the exclusive source of glomerular HGF when incubated with either iPS‐MSCs or BM‐MSCs in the presence of PA. Furthermore, both GEC‐derived HGF and exogenous recombinant HGF attenuated PA‐induced ER stress in cultured tubular cells, and this effect was abrogated by a neutralizing anti‐HGF antibody. Taken together, this study is the first to demonstrate that MSCs ameliorate lipotoxic kidney injury via a novel microenvironment‐dependent paracrine HGF/c‐Met signaling mechanism to suppress ER stress and its downstream pro‐inflammatory and pro‐apoptotic consequences.-
dc.languageeng-
dc.publisherWiley, published in association with AlphaMed Press. The Journal's web site is located at http://stemcellsjournals.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2157-6580/-
dc.relation.ispartofStem Cells Translational Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectEndoplasmic reticulum stress-
dc.subjectHepatocyte growth factor-
dc.subjectInduced pluripotent stem cells-
dc.subjectLipotoxicity-
dc.subjectMesenchymal stem cells-
dc.titleAmelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells Via Hepatocyte Growth Factor/c‐Met Signaling in Obesity‐Associated Kidney Injury-
dc.typeArticle-
dc.identifier.emailLeung, JCK: jckleung@hku.hk-
dc.identifier.emailChan, LYY: yychanb@hku.hk-
dc.identifier.emailYiu, WH: whyiu@hku.hk-
dc.identifier.emailLiu, WH: laurenwh@hku.hk-
dc.identifier.emailChan, KW: chriskwc@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.emailLai, KN: knlai@hku.hk-
dc.identifier.emailTang, SCW: scwtang@hku.hk-
dc.identifier.authorityLeung, JCK=rp00448-
dc.identifier.authorityTse, HF=rp00428-
dc.identifier.authorityLai, KN=rp00324-
dc.identifier.authorityTang, SCW=rp00480-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1002/sctm.18-0265-
dc.identifier.pmid31054183-
dc.identifier.scopuseid_2-s2.0-85065327049-
dc.identifier.hkuros299508-
dc.publisher.placeUnited States-

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