Podocyte injury is a critical step toward the progression of renal disease and is often associated with a loss of slit diaphragm proteins, including Podocin. Although there is a possibility that the extracellular domain of these slit diaphragm proteins can be a target for a pathological proteolysis, the precise mechanism driving the phenomenon remains unknown. Here we show that Matriptase, a membrane-anchored protein, was activated at podocytes in CKD patients and mice, whereas Matriptase inhibitors slowed the progression of mouse kidney disease. The mechanism could be accounted for by an imbalance favoring Matriptase over its cognate inhibitor, hepatocyte growth factor activator inhibitor type 1 (HAI-1), because conditional depletion of HAI-1 in podocytes accelerated podocyte injury in mouse model. Matriptase was capable of cleaving Podocin, but such a reaction was blocked by either HAI-1 or dominant-negative Matriptase. Furthermore, the N terminus of Podocin, as a consequence of Matriptase cleavage of Podocin, translocated to nucleoli, suggesting that the N terminus of Podocin might be involved in the process of podocyte injury. Given these observations, we propose that the proteolytic cleavage of Podocin by Matriptase could potentially cause podocyte injury and that targeting Matriptase could be a novel therapeutic strategy for CKD patients.

中文翻译：

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Matriptase 对 Podocin 的蛋白水解裂解加剧了足细胞损伤。

足细胞损伤是肾脏疾病进展的关键一步，通常与裂隙隔膜蛋白（包括足多辛）的丢失有关。尽管这些裂隙隔膜蛋白的细胞外结构域有可能成为病理性蛋白水解的目标，但驱动这种现象的确切机制仍然未知。在这里，我们展示了 Matriptase，一种膜锚定蛋白，在 CKD 患者和小鼠的足细胞中被激活，而 Matriptase 抑制剂减缓了小鼠肾脏疾病的进展。该机制可能是由于 Matriptase 与其同源抑制剂肝细胞生长因子激活剂抑制剂 1 型 (HAI-1) 的不平衡导致的，因为足细胞中 HAI-1 的条件性消耗加速了小鼠模型中的足细胞损伤。Matriptase 能够切割 Podocin，但这种反应被 HAI-1 或显性阴性 Matriptase 阻断。此外，由于 Podocin 的 Matriptase 裂解，Podocin 的 N 末端易位到核仁，表明 Podocin 的 N 末端可能参与了足细胞损伤的过程。鉴于这些观察结果，我们提出 Matriptase 对 Podocin 的蛋白水解裂解可能导致足细胞损伤，而靶向 Matriptase 可能是 CKD 患者的一种新治疗策略。