Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
Curr Opin Nephrol Hypertens. 2018 Jan;27(1):49-55. doi: 10.1097/MNH.0000000000000376.
Deregulation of protecting factor signaling actions in podocytes has emerged as an alternative pathway of podocyte injury mechanisms. Here, we review recent knowledge that highlighted how podocyte protecting factors are modulated by protein phosphatases.
Protein tyrosine kinases and phosphatases participate in many, if not all, aspects of cellular function by turning on or off multiple signaling cascades and podocytes are no exception. Modulation of tyrosine residue phosphorylation of podocyte factors such as nephrin, vascular endothelial growth factor, insulin receptors and substrates has been shown to promote podocyte damage and cell death that contributed to multiple glomerular diseases. Protein phosphatase activity can cause either an increase [Src homology 2 domain-containing phosphatase 2 (SHP-2)] or a decrease [Protein tyrosine phosphatase1B (PTP1B), SHP-1 and SH2 domain-containing 5'-inositol phosphatase 2 (SHIP2)] in nephrin tyrosine phosphorylation depending on which podocyte injury model was used. Insulin resistance is closely linked to the development and progression of renal disease. Expression of PTP1B, SHP-1, phosphatase and tensin homolog and SHIP2 are potential mechanisms of podocytes insulin resistance in diabetic kidney disease.
Tight regulation of protein phosphatases is critical to maintain cell homeostasis and may offer new perceptive targets to restore protecting factor actions in order to prevent podocyte dysfunction and glomerular diseases.
足细胞保护因子信号转导失调作为足细胞损伤机制的另一种途径已经出现。在这里，我们回顾了最近的知识，强调了足细胞保护因子如何被蛋白磷酸酶调节。
蛋白酪氨酸激酶和磷酸酶通过开启或关闭多个信号级联反应参与了许多（如果不是全部）细胞功能，而足细胞也不例外。已经表明，调节足细胞因子如nephrin、血管内皮生长因子、胰岛素受体和底物的酪氨酸残基磷酸化会导致足细胞损伤和细胞死亡，从而导致多种肾小球疾病。蛋白磷酸酶活性可以根据使用的足细胞损伤模型，导致nephrin 酪氨酸磷酸化的增加（Src 同源 2 结构域磷酸酶 2 (SHP-2)）或减少（蛋白酪氨酸磷酸酶 1B (PTP1B)、SHP-1 和 SH2 结构域含有 5'-肌醇磷酸酶 2 (SHIP2)）。胰岛素抵抗与肾脏疾病的发生和进展密切相关。糖尿病肾病中 PTP1B、SHP-1、磷酸酶和张力蛋白同源物和 SHIP2 的表达是足细胞胰岛素抵抗的潜在机制。
蛋白磷酸酶的严格调节对于维持细胞内稳态至关重要，并可能为恢复保护因子作用提供新的靶点，以防止足细胞功能障碍和肾小球疾病。
