Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria.
Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria.
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DOI：
10.1038/s41598-017-00564-3
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发表时间：
2017-03-28
影响因子：
4.6
通讯作者：
Haj FG
中科院分区：
文献类型：
--
作者：
Hsu MF;Bettaieb A;Ito Y;Graham J;Havel PJ;Haj FG
足细胞是特化的上皮细胞，其在维持肾小球滤过屏障的完整性和防止尿蛋白渗漏中起重要作用。我们研究了蛋白酪氨酸磷酸酶Shp 2在脂多糖（LPS）诱导的肾损伤中的作用。我们报告增加Shp 2表达在小鼠肾脏和培养足细胞后，LPS的挑战。为了确定足细胞Shp 2在体内的作用，我们产生了足细胞特异性Shp 2敲除（pod-Shp 2 KO）小鼠。在给予LPS后，pod-Shp 2 KO小鼠表现出比对照组更低的蛋白尿和血尿素氮浓度，表明保持了滤器完整性。此外，与对照组相比，LPS处理的敲除小鼠的肾脏mRNA和炎性细胞因子IL-1β、TNFα、INFγ和IL-12 p70的血清浓度显著降低。此外，足细胞Shp 2缺陷的保护作用与LPS诱导的NF-κB和MAPK活化减少、nephrin磷酸化和内质网应激减弱有关。这些效果在分化的E11小鼠足细胞中用慢病毒介导的Shp 2敲低重现。此外，Shp 2缺陷足细胞在伤口愈合测定中显示出减少的LPS诱导的迁移。这些发现将足细胞中的Shp 2鉴定为LPS攻击后信号传导事件的重要贡献者，并表明抑制足细胞中的Shp 2可能是足细胞病变的潜在治疗靶点。
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.