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

Ming Fo Hsu, Ahmed Bettaieb, Yoshihiro Ito, James Graham, Peter J Havel, Fawaz Haj

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article number461
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Podocytes
Protein Tyrosine Phosphatases
Proteinuria
Lipopolysaccharides
Knockout Mice
Kidney
Glomerular Filtration Barrier
Endoplasmic Reticulum Stress
Blood Urea Nitrogen
Interleukin-12
Interleukin-1
Wound Healing
Epithelial Cells
Phosphorylation
Cytokines

ASJC Scopus subject areas

  • General

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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.

In: Scientific Reports, Vol. 7, No. 1, 461, 01.12.2017.

Research output: Contribution to journalArticle

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