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Sci Rep. 2017 Mar 28;7(1):461. doi: 10.1038/s41598-017-00564-3.

Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria.

Author information

1
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
2
Department of Nutrition, University of Tennessee-Knoxville, Knoxville, TN, 37996, USA.
3
Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
4
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA. fghaj@ucdavis.edu.
5
Comprehensive Cancer Center, University of California Davis, Sacramento, CA, 95817, USA. fghaj@ucdavis.edu.
6
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA, 95817, USA. fghaj@ucdavis.edu.

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.

PMID:
28352079
PMCID:
PMC5428720
DOI:
10.1038/s41598-017-00564-3
[Indexed for MEDLINE]
Free PMC Article

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