Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria
Abstract 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 i...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-00564-3 |
| _version_ | 1818856115030458368 |
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| author | Ming-Fo Hsu Ahmed Bettaieb Yoshihiro Ito James Graham Peter J. Havel Fawaz G. Haj |
| author_facet | Ming-Fo Hsu Ahmed Bettaieb Yoshihiro Ito James Graham Peter J. Havel Fawaz G. Haj |
| author_sort | Ming-Fo Hsu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T08:19:22Z |
| format | Article |
| id | doaj.art-596de7c5fb144f74bc697024e074dc19 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T08:19:22Z |
| publishDate | 2017-03-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-596de7c5fb144f74bc697024e074dc192022-12-21T20:29:25ZengNature PortfolioScientific Reports2045-23222017-03-017111310.1038/s41598-017-00564-3Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuriaMing-Fo Hsu0Ahmed Bettaieb1Yoshihiro Ito2James Graham3Peter J. Havel4Fawaz G. Haj5Department of Nutrition, University of California DavisDepartment of Nutrition, University of California DavisDepartment of Nutrition, University of California DavisDepartment of Nutrition, University of California DavisDepartment of Nutrition, University of California DavisDepartment of Nutrition, University of California DavisAbstract 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.https://doi.org/10.1038/s41598-017-00564-3 |
| spellingShingle | Ming-Fo Hsu Ahmed Bettaieb Yoshihiro Ito James Graham Peter J. Havel Fawaz G. Haj Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria Scientific Reports |
| 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 |
| url | https://doi.org/10.1038/s41598-017-00564-3 |
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