Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and effective treatment modalities that fully address its molecular etiology are lacking. Prior studies support that the stress response protein REDD1 (Regulated in Development and DNA Damage 1) contributes to the development of diabetic complications. This study investigated a potential role for REDD1 expression in podocytes in diabetes-induced podocyte loss and compromised glomerular filtration. Podocyte-specific REDD1 deletion protected against renal injury, as evidenced by reduced albuminuria, glomerular hypertrophy, and mesangial matrix deposition in streptozotocin (STZ)-induced diabetic mice. Podocyte-specific REDD1 expression was required for diabetes-induced reduction in slit diaphragm (SD) proteins podocin and nephrin. Notably, podocyte-specific REDD1 deletion protected against podocytopenia and preserved glomerular basement membrane and foot process architecture in diabetic mice. In the kidneys of diabetic mice and in human podocyte cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the transient receptor potential canonical 6 (TRPC6) channel. More specifically, REDD1 promoted NF-κB-dependent transcription of TRPC6, intracellular calcium entry, and cytoskeletal remodeling under hyperglycemic conditions. Overall, the findings provide new insight into the role of podocyte-specific REDD1 expression in renal pathology and support the possibility that therapeutics targeting REDD1 in podocytes could be beneficial for DN.

中文翻译：

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应激反应蛋白 REDD1 的足细胞特异性表达对于糖尿病引起的足细胞减少症是必要的


糖尿病肾病（DN）是终末期肾病的主要原因，但缺乏充分解决其分子病因学的有效治疗方式。先前的研究支持应激反应蛋白 REDD1（发育和 DNA 损伤调节 1）有助于糖尿病并发症的发生。这项研究调查了足细胞中 REDD1 表达在糖尿病引起的足细胞丢失和肾小球滤过受损中的潜在作用。足细胞特异性 REDD1 缺失可以防止肾损伤，链脲佐菌素 (STZ) 诱导的糖尿病小鼠中白蛋白尿、肾小球肥大和系膜基质沉积减少就证明了这一点。足细胞特异性 REDD1 表达是糖尿病引起的狭缝隔膜 (SD) 蛋白足多辛 (podocin) 和去氧肾上腺素 (nephrin) 减少所必需的。值得注意的是，足细胞特异性 REDD1 缺失可防止糖尿病小鼠出现足细胞减少症，并保留肾小球基底膜和足突结构。在糖尿病小鼠的肾脏和暴露于高血糖条件下的人类足细胞培养物中，REDD1 对于瞬时受体电位规范 6 (TRPC6) 通道表达的增加是必需的。更具体地说，REDD1 在高血糖条件下促进 TRPC6 的 NF-κB 依赖性转录、细胞内钙进入和细胞骨架重塑。总体而言，这些发现为足细胞特异性 REDD1 表达在肾脏病理学中的作用提供了新的见解，并支持针对足细胞中 REDD1 的治疗可能有益于 DN 的可能性。