Roux-en-Y Gastric Bypass Reduces Podocyte Injury in Diabetic Kidney Disease

Podocyte injury in diabetic kidney disease contributes to the development of albuminuria and subsequent renal decline. Clinically, gastric bypass surgery is associated with reductions in albuminuria, and rodent studies demonstrate coherent improvements in renal histology. We aimed to investigate the mechanisms underpinning remission of albuminuria following gastric bypass focussing on podocyte injury. Firstly, we tracked the evolution of albuminuria and cognate evidence of histological and ultrastructural damage to the glomerulus in male Zucker Diabetic Fatty rats. Secondly, we examined the impact of gastric bypass in these rats, focussing on podocyte injury. Thirdly, we conducted a global transcriptomic study profiling the shift in the renal transcriptome in the Zucker Diabetic Fatty rats rat and its relevance to human disease. Lastly, we explored whether gastric bypass could reverse the changes seen in the disease associated transcriptome. Albuminuria in the Zucker Diabetic Fatty rat developed by 12 weeks of age. This was accompanied by glomerulomegaly, podocyte stress and ultrastructural evidence of podocyte dedifferentiation. When animals underwent gastric bypass at 12 weeks of age, marked reductions in albuminuria in association with normalisation of glomerular tuft size, attenuation of podocyte stress and improvements in podocyte foot process morphology were observed within 2 months of surgery. A characteristic disease associated gene expression signature was observed in the kidneys of Zucker Diabetic Fatty rats, with a core set of alterations conserved in global analysis of the human DKD transcriptome. Many of the shared gene expression alterations were reversed by gastric bypass. Reductions in podocyte injury represent a key mechanism underpinning the remission of albuminuria following gastric bypass.糖尿病肾病（Diabetic Kidney Disease, DKD）中的足细胞（podocyte）损伤，可推动白蛋白尿（albuminuria）的发生及后续肾功能下降。临床研究显示，胃旁路手术（gastric bypass surgery）与白蛋白尿水平降低存在相关性，而啮齿类动物实验证实肾脏组织学可出现一致性改善。本研究旨在探究胃旁路术后白蛋白尿缓解的潜在机制，重点聚焦足细胞损伤。 首先，我们对雄性Zucker糖尿病肥胖（Zucker Diabetic Fatty, ZDF）大鼠的白蛋白尿进展，以及肾小球（glomerulus）组织学与超微结构（ultrastructural）损伤的相关证据进行了追踪；其次，我们评估了胃旁路手术对该类大鼠的影响，重点聚焦足细胞损伤；第三，我们开展了全转录组学（transcriptomic）研究，分析Zucker糖尿病肥胖大鼠肾脏转录组的变化特征，及其与人类疾病的相关性；最后，我们探究了胃旁路手术是否能够逆转疾病相关转录组的异常改变。 Zucker糖尿病肥胖大鼠的白蛋白尿在12周龄时出现，同时伴随肾小球肥大、足细胞应激以及足细胞去分化的超微结构证据。当大鼠于12周龄接受胃旁路手术后，术后2个月内即可观察到白蛋白尿显著降低，同时伴随肾小球簇体积恢复正常、足细胞应激减轻以及足细胞足突形态改善。 Zucker糖尿病肥胖大鼠的肾脏中可观察到特征性的疾病相关基因表达谱，其核心异常改变在人类糖尿病肾病转录组的整体分析中也具有保守性。多数共有的基因表达异常可通过胃旁路手术得到逆转。 足细胞损伤的减轻，是胃旁路术后白蛋白尿缓解的关键机制。