Department of Pediatrics, Peking University First Hospital, No.1, Xi An Men Da Jie, 100034, Beijing, People's Republic of China.
Mol Biol Rep. 2010 Jun;37(5):2477-84. doi: 10.1007/s11033-009-9761-6. Epub 2009 Aug 29.
Podocyte and its slit diaphragm play an important role in maintaining normal glomerular filtration barrier function and structure. Podocyte apoptosis and slit diaphragm injury leads to proteinuria and glomerulosclerosis. However, the molecular mechanism of podocyte injury remains poorly understood. The family of mitogen-activated protein kinases including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase, and p38 signal pathways, are implicated in the progression of various glomerulopathies. However, the role of the activated signal pathway(s) in podocyte injury is elusive. This study examined phosphorylation of ERK in rat puromycin aminonucleoside (PAN) nephropathy as well as conditionally immortalized mouse podocyte treated with PAN in vitro. The effect of treatment with U0126, an inhibitor of ERK, was also investigated. In PAN nephropathy, the phosphorylation of ERK was marked. In podocyte injury, the marked and sustained activation of ERK pathway was also observed before the appearance of significant podocyte apoptosis. Pretreatment with U0126 to podocyte completely inhibited ERK activation, with complete suppression podocyte apoptosis and ameliorated nephrin protein expression along with the phosphorylation of nephrin in podocyte injury. In cultured podocyte, PAN induced actin recorganition, and U0126 inhibited such change. However, U0126 did not recovery the phosphorylation change of neph1 in podocyte injury. We concluded that the sustained activation of ERK along with the phosphorylation of neph1 might be necessary for podocyte injury. The study here suggested that ERK might become a potential target for therapeutic intervention to prevent podocytes from injury which will result in proteinuria.
足细胞及其裂孔隔膜在维持正常肾小球滤过屏障功能和结构中发挥着重要作用。足细胞凋亡和裂孔隔膜损伤导致蛋白尿和肾小球硬化。然而，足细胞损伤的分子机制仍知之甚少。丝裂原活化蛋白激酶家族包括细胞外信号调节激酶（ERK）、c-Jun N-末端激酶和 p38 信号通路，与各种肾小球疾病的进展有关。然而，激活的信号通路（s）在足细胞损伤中的作用尚不清楚。本研究检测了嘌呤霉素氨基核苷（PAN）肾病大鼠和体外培养的条件永生化小鼠足细胞中 ERK 的磷酸化。还研究了 ERK 抑制剂 U0126 的作用。在 PAN 肾病中，ERK 的磷酸化很明显。在足细胞损伤中，在明显的足细胞凋亡出现之前，ERK 途径也观察到明显和持续的激活。U0126 预处理足细胞完全抑制 ERK 激活，完全抑制足细胞凋亡，并改善足细胞损伤中nephrin 蛋白的表达以及 nephrin 的磷酸化。在培养的足细胞中，PAN 诱导肌动蛋白重排，U0126 抑制这种变化。然而，U0126 并没有恢复足细胞损伤中 neph1 的磷酸化变化。我们得出结论，ERK 的持续激活以及 neph1 的磷酸化可能是足细胞损伤所必需的。本研究表明，ERK 可能成为治疗干预的潜在靶点，以防止足细胞损伤导致蛋白尿。
