Division of Nephrology, Stead Family Department of Pediatrics, The University of Iowa, Iowa City, Iowa.
Carver College of Medicine, The University of Iowa, Iowa City, Iowa.
Kidney360. 2023 Feb 1;4(2):162-176. doi: 10.34067/KID.0006852022. Epub 2022 Dec 6.
The expression of dynein is increased in human and rodent models of diabetic nephropathy (DN), eliciting a new dynein-driven pathogenesis. Uncontrolled dynein impairs the molecular sieve of kidney by remodeling the postendocytic triage and homeostasis of nephrin. The delineation of the dynein-driven pathogenesis promises a broad spectrum of new therapeutic targets for human DN.
Diabetic nephropathy (DN) is characterized by increased endocytosis and degradation of nephrin, a protein that comprises the molecular sieve of the glomerular filtration barrier. While nephrin internalization has been found activated in diabetes-stressed podocytes, the postinternalization trafficking steps that lead to the eventual depletion of nephrin and the development of DN are unclear. Our work on an inherited podocytopathy uncovered that dysregulated dynein could compromise nephrin trafficking, leading us to test whether and how dynein mediates the pathogenesis of DN.
We analyzed the transcription of dynein components in public DN databases, using the platform. We verified altered dynein transcription in diabetic podocytopathy by quantitative PCR. Dynein-mediated trafficking and degradation of nephrin was investigated using an nephrin trafficking model and was demonstrated in a mouse model with streptozotocin (STZ)-induced DN and in human kidney biopsy sections.
Our transcription analysis revealed increased expression of dynein in human DN and diabetic mouse kidney, correlated significantly with the severity of hyperglycemia and DN. In diabetic podocytopathy, we observed that dynein-mediated postendocytic sorting of nephrin was upregulated, resulting in accelerated nephrin degradation and disrupted nephrin recycling. In hyperglycemia-stressed podocytes, , one of the most upregulated dynein components, is required for the recruitment of dynein complex that mediates the postendocytic sorting of nephrin. This was corroborated by observing enhanced Dynll1-nephrin colocalization in podocytes of diabetic patients, as well as dynein-mediated trafficking and degradation of nephrin in STZ-induced diabetic mice with hyperglycemia. Knockdown of attenuated lysosomal degradation of nephrin and promoted its recycling, suggesting the essential role of Dynll1 in dynein-mediated mistrafficking.
Our studies show that hyperglycemia stimulates dynein-mediated trafficking of nephrin to lysosomes by inducing its expression. The decoding of dynein-driven pathogenesis of diabetic podocytopathy offers a spectrum of new dynein-related therapeutic targets for DN.
动力蛋白在人类和啮齿动物糖尿病肾病（DN）模型中的表达增加，引发了新的动力蛋白驱动的发病机制。失控的动力蛋白通过重塑足细胞内吞后的分类和nephrin 的稳态，损害了肾脏的分子筛。动力蛋白驱动的发病机制的描绘为人类 DN 提供了广泛的新治疗靶点。
糖尿病肾病（DN）的特征是内吞作用和nephrin 的降解增加，nephrin 是构成肾小球滤过屏障分子筛的一种蛋白质。虽然已经发现糖尿病应激足细胞中 nephrin 的内化被激活，但导致 nephrin 最终耗竭和 DN 发展的内化后转运步骤尚不清楚。我们在遗传性足细胞病中的研究发现，失调的动力蛋白可能会损害 nephrin 的运输，这促使我们测试动力蛋白是否以及如何介导 DN 的发病机制。
我们使用 平台分析了公共 DN 数据库中动力蛋白成分的转录。我们通过定量 PCR 验证了糖尿病性足细胞病变中 dynein 转录的改变。使用 nephrin 运输模型研究了 dynein 介导的 nephrin 运输和降解，并在链脲佐菌素（STZ）诱导的 DN 小鼠模型和人类肾活检切片中进行了验证。
我们的转录分析显示，人类 DN 和糖尿病小鼠肾脏中的 dynein 表达增加，与高血糖的严重程度和 DN 显著相关。在糖尿病性足细胞病变中，我们观察到 dynein 介导的 nephrin 内化后分类被上调，导致 nephrin 降解加速和 nephrin 循环破坏。在高血糖应激的足细胞中，dynactin 复合物的募集需要动力蛋白成分中上调最明显的之一，dynactin 复合物介导 nephrin 的内化后分类。在糖尿病患者的足细胞中观察到 Dynll1-nephrin 共定位增强，以及在高血糖的 STZ 诱导的糖尿病小鼠中 dynein 介导的 nephrin 运输和降解，证实了这一点。dynactin 的敲低减弱了 nephrin 的溶酶体降解，并促进了其回收，表明 Dynll1 在 dynein 介导的运输错误中起关键作用。
我们的研究表明，高血糖通过诱导其表达刺激 dynein 介导的 nephrin 向溶酶体的运输。对糖尿病性足细胞病中 dynein 驱动的发病机制的解码为 DN 提供了一系列新的 dynein 相关治疗靶点。
