Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury.
Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury.
复制标题
DOI：
10.1016/j.metabol.2017.07.009
复制
发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Haj FG
中科院分区：
文献类型：
--
作者：
Ito Y;Hsu MF;Bettaieb A;Koike S;Mello A;Calvo-Rubio M;Villalba JM;Haj FG
糖尿病肾病是糖尿病最具破坏性的并发症之一，越来越多的证据表明足细胞功能障碍与疾病发病机制有关。本研究的目的是探讨足细胞中蛋白酪氨酸磷酸酶 1B (PTP1B) 对高血糖诱导的肾损伤的影响。为了确定 PTP1B 在足细胞中的体内功能，我们生成了足细胞特异性 PTP1B 破坏的小鼠（以下称为 pod-PTP1B KO）。在正常血糖和高脂饮食（HFD）和链脲佐菌素（STZ）诱导的高血糖下测定对照小鼠和 pod-PTP1B KO 小鼠的肾功能。 HFD 和 STZ 攻击后，小鼠肾脏中 PTP1B 表达增加。在正常血糖控制下，pod-PTP1B KO 小鼠表现出相当的肾功能。然而，足细胞 PTP1B 破坏减轻了高血糖引起的蛋白尿和肾损伤，并保持了血糖控制。此外，足细胞 PTP1B 破坏还伴随着肾脏胰岛素信号传导的改善和自噬的增强，从而减少了炎症和纤维化。此外，通过慢病毒介导的 PTP1B 敲低，在 E11 小鼠足细胞中重现了体内足细胞 PTP1B 破坏的有益效果。敲低足细胞中 PTP1B 的重建逆转了增强的胰岛素信号传导和自噬，表明它们可能是 PTP1B 缺陷的结果。此外，PTP1B 敲低足细胞中自噬的药理减弱减轻了 PTP1B 缺陷的保护作用。这些发现表明，足细胞 PTP1B 缺陷可减轻高血糖引起的肾损伤，并表明 PTP1B 可能是肾损伤的治疗靶点。
Diabetic nephropathy is one of the most devastating complications of diabetes, and growing evidence implicates podocyte dysfunction in disease pathogenesis. The objective of this study was to investigate the contribution of protein tyrosine phosphatase 1B (PTP1B) in podocytes to hyperglycemia-induced renal injury. To determine the in vivo function of PTP1B in podocytes we generated mice with podocyte-specific PTP1B disruption (hereafter termed pod-PTP1B KO). Kidney functions were determined in control and pod-PTP1B KO mice under normoglycemia and high-fat diet (HFD)- and streptozotocin (STZ)-induced hyperglycemia. PTP1B expression increased in murine kidneys following HFD and STZ challenges. Under normoglycemia control and pod-PTP1B KO mice exhibited comparable renal functions. However, podocyte PTP1B disruption attenuated hyperglycemia-induced albuminuria and renal injury and preserved glucose control. Also, podocyte PTP1B disruption was accompanied with improved renal insulin signaling and enhanced autophagy with decreased inflammation and fibrosis. Moreover, the beneficial effects of podocyte PTP1B disruption in vivo were recapitulated in E11 murine podocytes with lentiviral-mediated PTP1B knockdown. Reconstitution of PTP1B in knockdown podocytes reversed the enhanced insulin signaling and autophagy suggesting that they were likely a consequence of PTP1B deficiency. Further, pharmacological attenuation of autophagy in PTP1B knockdown podocytes mitigated the protective effects of PTP1B deficiency. These findings demonstrate that podocyte PTP1B deficiency attenuates hyperglycemia-induced renal damage and suggest that PTP1B may present a therapeutic target in renal injury.
登录
查看更多内容
影响因子：
7.7
作者：
Delibegovic M;Zimmer D;Kauffman C;Rak K;Hong EG;Cho YR;Kim JK;Kahn BB;Neel BG;Bence KK
通讯作者：
Bence KK
影响因子：
21.3
作者：
Dadke, Shrikrishna;Cotteret, Sophie;Chernoff, Jonathan
通讯作者：
Chernoff, Jonathan
影响因子：
7.7
作者：
Grant, Louise;Shearer, Kirsty D.;Delibegovic, Mirela
通讯作者：
Delibegovic, Mirela
影响因子：
15.9
作者：
Banno, Ryoichi;Zimmer, Derek;Bence, Kendra K.
通讯作者：
Bence, Kendra K.
DOI：
10.1155/2011/376543
发表时间：
2011
期刊：
Journal of signal transduction
影响因子：
--
作者：
Aoudjit L;Jiang R;Lee TH;New LA;Jones N;Takano T
通讯作者：
Takano T