Defects in protein reabsorption by the proximal tubule are toxic for epithelial cells in the nephron and may result in nephropathy. In this study, we showed that the ion channel TRPV4 modulated the endocytosis of albumin and low–molecular weight proteins in the proximal tubule. TRPV4 was found at the basolateral side of proximal tubule cells, and its mechanical activation by cell stretching induced Ca²⁺ entry into the cytosol, which promoted endocytosis. Trpv4^−/− mice presented with mild proximal tubule dysfunction under basal conditions. To challenge endocytic function, the permeability of the glomerular filter was altered by systemic delivery of angiotensin II. The proteinuria induced by this treatment was more severe in Trpv4^−/− than in Trpv4^+/+ mice. Injecting antibodies against the glomerular basement membrane to induce glomerulonephritis is a more pathophysiologically relevant method of impairing glomerular filter permeability. Albuminuria was more severe in mice that lacked TRPV4 specifically in the proximal tubule than in control mice. These results emphasize the importance of TRPV4 in sensing pressure in the proximal tubule in response to variations in the amount of ultrafiltrate and unveil a mechanism that controls protein reabsorption.

近端小管对蛋白质的重吸收缺陷对肾单位中的上皮细胞有毒，并可能导致肾病。在这项研究中，我们发现离子通道 TRPV4 调节近端小管中白蛋白和低分子量蛋白质的内吞作用。在近端小管细胞的基底外侧发现了 TRPV4，它通过细胞拉伸的机械激活诱导 Ca ²⁺进入细胞质，促进内吞作用。Trpv4 ^-/-小鼠在基础条件下呈现轻度近端小管功能障碍。为了挑战内吞功能，血管紧张素 II 的全身递送改变了肾小球滤器的通透性。这种治疗引起的蛋白尿在Trpv4 ^{-/- 中}更为严重比Trpv4 ^+/+小鼠。注射针对肾小球基底膜的抗体以诱发肾小球肾炎是一种损害肾小球滤过器通透性的更病理生理相关的方法。与对照小鼠相比，在近端小管中特异性缺乏 TRPV4 的小鼠的白蛋白尿更严重。这些结果强调了 TRPV4 在感应近端小管压力以响应超滤液量变化中的重要性，并揭示了控制蛋白质重吸收的机制。