![]() Podocytes are highly differentiated, epithelial cells that encapsulate the glomerular capillary loops. 2–4 However, we lack a clear understanding of how hyperglycemia directly causes kidney injury, which in turn limits our ability to develop effective therapies. 1 Hyperglycemia and associated glomerular hyperperfusion are considered the major causes of DN tight glucose control has clearly been shown to reduce the incidence of microalbuminuria and postpone the development of DN. The decoding of dynein-driven pathogenesis of diabetic podocytopathy offers a spectrum of new dynein-related therapeutic targets for DN.ĭiabetic nephropathy (DN) is the most prevalently acquired podocytopathy in humans and contributes to more than 50% of the cases of end-stage glomerulopathy. Our studies show that hyperglycemia stimulates dynein-mediated trafficking of nephrin to lysosomes by inducing its expression. Knockdown of Dynll1 attenuated lysosomal degradation of nephrin and promoted its recycling, suggesting the essential role of Dynll1 in dynein-mediated mistrafficking. 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. In hyperglycemia-stressed podocytes, Dynll1, one of the most upregulated dynein components, is required for the recruitment of dynein complex that mediates the postendocytic sorting of nephrin. In diabetic podocytopathy, we observed that dynein-mediated postendocytic sorting of nephrin was upregulated, resulting in accelerated nephrin degradation and disrupted nephrin recycling. Our transcription analysis revealed increased expression of dynein in human DN and diabetic mouse kidney, correlated significantly with the severity of hyperglycemia and DN. ![]() Dynein-mediated trafficking and degradation of nephrin was investigated using an in vitro nephrin trafficking model and was demonstrated in a mouse model with streptozotocin (STZ)-induced DN and in human kidney biopsy sections. We verified altered dynein transcription in diabetic podocytopathy by quantitative PCR. We analyzed the transcription of dynein components in public DN databases, using the Nephroseq platform. 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. ![]() 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.
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