title: 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 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.
authors.affiliation: Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
authors.forename: Ming-Fo
authors.initials: MF
authors.lastname: Hsu
authors.affiliation: Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.|Department of Nutrition, University of Tennessee-Knoxville, Knoxville, TN, 37996, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.affiliation: Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.|Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
authors.forename: James
authors.initials: J
authors.lastname: Graham
authors.affiliation: Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.|Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
authors.affiliation: Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA. fghaj@ucdavis.edu.|Comprehensive Cancer Center, University of California Davis, Sacramento, CA, 95817, USA. fghaj@ucdavis.edu.|Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA, 95817, USA. fghaj@ucdavis.edu.
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
mesh_terms: D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics; D004198:Disease Susceptibility; D015870:Gene Expression; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000009:adverse effects*; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology* / Q000378:metabolism* / Q000652:urine
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11