Cargando…
Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria
Podocytes are specialized epithelial cells that play a significant role in maintaining the integrity of the glomerular filtration barrier and preventing urinary protein leakage. We investigated the contribution of protein tyrosine phosphatase Shp2 to lipopolysaccharide (LPS)-induced renal injury. We...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428720/ https://www.ncbi.nlm.nih.gov/pubmed/28352079 http://dx.doi.org/10.1038/s41598-017-00564-3 |
_version_ | 1783235886362656768 |
---|---|
author | Hsu, Ming-Fo Bettaieb, Ahmed Ito, Yoshihiro Graham, James Havel, Peter J. Haj, Fawaz G. |
author_facet | Hsu, Ming-Fo Bettaieb, Ahmed Ito, Yoshihiro Graham, James Havel, Peter J. Haj, Fawaz G. |
author_sort | Hsu, Ming-Fo |
collection | PubMed |
description | Podocytes are specialized epithelial cells that play a significant role in maintaining the integrity of the glomerular filtration barrier and preventing urinary protein leakage. We investigated the contribution of protein tyrosine phosphatase Shp2 to lipopolysaccharide (LPS)-induced renal injury. We report increased Shp2 expression in murine kidneys and cultured podocytes following an LPS challenge. To determine the role of podocyte Shp2 in vivo, we generated podocyte-specific Shp2 knockout (pod-Shp2 KO) mice. Following administration of LPS, pod-Shp2 KO mice exhibited lower proteinuria and blood urea nitrogen concentrations than controls indicative of preserved filter integrity. In addition, renal mRNA and serum concentrations of inflammatory cytokines IL-1β, TNFα, INFγ and IL-12 p70 were significantly decreased in LPS-treated knockout mice compared with controls. Moreover, the protective effects of podocyte Shp2 deficiency were associated with decreased LPS-induced NF-κB and MAPK activation, nephrin phosphorylation and attenuated endoplasmic reticulum stress. These effects were recapitulated in differentiated E11 murine podocytes with lentiviral-mediated Shp2 knockdown. Furthermore, Shp2 deficient podocytes displayed reduced LPS-induced migration in a wound healing assay. These findings identify Shp2 in podocytes as a significant contributor to the signaling events following LPS challenge and suggest that inhibition of Shp2 in podocytes may present a potential therapeutic target for podocytopathies. |
format | Online Article Text |
id | pubmed-5428720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-54287202017-05-15 Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria Hsu, Ming-Fo Bettaieb, Ahmed Ito, Yoshihiro Graham, James Havel, Peter J. Haj, Fawaz G. Sci Rep Article Podocytes are specialized epithelial cells that play a significant role in maintaining the integrity of the glomerular filtration barrier and preventing urinary protein leakage. We investigated the contribution of protein tyrosine phosphatase Shp2 to lipopolysaccharide (LPS)-induced renal injury. We report increased Shp2 expression in murine kidneys and cultured podocytes following an LPS challenge. To determine the role of podocyte Shp2 in vivo, we generated podocyte-specific Shp2 knockout (pod-Shp2 KO) mice. Following administration of LPS, pod-Shp2 KO mice exhibited lower proteinuria and blood urea nitrogen concentrations than controls indicative of preserved filter integrity. In addition, renal mRNA and serum concentrations of inflammatory cytokines IL-1β, TNFα, INFγ and IL-12 p70 were significantly decreased in LPS-treated knockout mice compared with controls. Moreover, the protective effects of podocyte Shp2 deficiency were associated with decreased LPS-induced NF-κB and MAPK activation, nephrin phosphorylation and attenuated endoplasmic reticulum stress. These effects were recapitulated in differentiated E11 murine podocytes with lentiviral-mediated Shp2 knockdown. Furthermore, Shp2 deficient podocytes displayed reduced LPS-induced migration in a wound healing assay. These findings identify Shp2 in podocytes as a significant contributor to the signaling events following LPS challenge and suggest that inhibition of Shp2 in podocytes may present a potential therapeutic target for podocytopathies. Nature Publishing Group UK 2017-03-28 /pmc/articles/PMC5428720/ /pubmed/28352079 http://dx.doi.org/10.1038/s41598-017-00564-3 Text en © The Author(s) 2017 This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Hsu, Ming-Fo Bettaieb, Ahmed Ito, Yoshihiro Graham, James Havel, Peter J. Haj, Fawaz G. Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria |
title | Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria |
title_full | Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria |
title_fullStr | Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria |
title_full_unstemmed | Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria |
title_short | Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria |
title_sort | protein tyrosine phosphatase shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428720/ https://www.ncbi.nlm.nih.gov/pubmed/28352079 http://dx.doi.org/10.1038/s41598-017-00564-3 |
work_keys_str_mv | AT hsumingfo proteintyrosinephosphataseshp2deficiencyinpodocytesattenuateslipopolysaccharideinducedproteinuria AT bettaiebahmed proteintyrosinephosphataseshp2deficiencyinpodocytesattenuateslipopolysaccharideinducedproteinuria AT itoyoshihiro proteintyrosinephosphataseshp2deficiencyinpodocytesattenuateslipopolysaccharideinducedproteinuria AT grahamjames proteintyrosinephosphataseshp2deficiencyinpodocytesattenuateslipopolysaccharideinducedproteinuria AT havelpeterj proteintyrosinephosphataseshp2deficiencyinpodocytesattenuateslipopolysaccharideinducedproteinuria AT hajfawazg proteintyrosinephosphataseshp2deficiencyinpodocytesattenuateslipopolysaccharideinducedproteinuria |