Ito Yoshihiro, Hsu Ming-Fo, Bettaieb Ahmed, Koike Shinichiro, Mello Aline, Calvo-Rubio Miguel, Villalba Jose M, Haj Fawaz G
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, United States.
Department of Cell Biology, Physiology and Immunology, Agrifood Campus of International Excellence ceiA3, University of Cordoba, 14014 Cordoba, Spain.
Metabolism. 2017 Nov;76:56-69. doi: 10.1016/j.metabol.2017.07.009. Epub 2017 Aug 8.
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.
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参与了疾病的发病机制。本研究的目的是探讨足细胞中蛋白酪氨酸磷酸酶1B（PTP1B）在高血糖诱导的肾损伤中的作用。
为了确定PTP1B在足细胞中的体内功能，我们构建了足细胞特异性PTP1B缺失的小鼠（以下简称足细胞-PTP1B基因敲除小鼠）。在正常血糖以及高脂饮食（HFD）和链脲佐菌素（STZ）诱导的高血糖条件下，测定对照小鼠和足细胞-PTP1B基因敲除小鼠的肾功能。
HFD和STZ刺激后，小鼠肾脏中PTP1B表达增加。在正常血糖条件下，对照小鼠和足细胞-PTP1B基因敲除小鼠的肾功能相当。然而，足细胞PTP1B缺失减轻了高血糖诱导的蛋白尿和肾损伤，并维持了血糖控制。此外，足细胞PTP1B缺失伴随着肾胰岛素信号改善、自噬增强，炎症和纤维化减少。此外，在E11小鼠足细胞中通过慢病毒介导的PTP1B敲低再现了足细胞PTP1B缺失在体内的有益作用。在敲低的足细胞中重建PTP1B可逆转增强的胰岛素信号和自噬，表明它们可能是PTP1B缺乏的结果。此外，PTP1B敲低的足细胞中自噬的药理学减弱减轻了PTP1B缺乏的保护作用。
这些发现表明足细胞PTP1B缺乏减轻了高血糖诱导的肾损伤，并提示PTP1B可能是肾损伤的一个治疗靶点。
