Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Electron Microscopy Lab, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Diabetes. 2022 May 1;71(5):1073-1080. doi: 10.2337/db21-0645.
The pdx1-/- zebrafish mutant was recently established as a novel animal model of diabetic retinopathy. In this study, we investigate whether knockout of pdx1 also leads to diabetic kidney disease (DKD). pdx1-/- larvae exhibit several signs of early DKD, such as glomerular hypertrophy, impairments in the filtration barrier corresponding to microalbuminuria, and glomerular basement membrane (GBM) thickening. Adult pdx1-/- mutants show progressive GBM thickening in comparison with the larval state. Heterozygous pdx1 knockout also leads to glomerular hypertrophy as initial establishment of DKD similar to the pdx1-/- larvae. RNA sequencing of adult pdx1+/- kidneys uncovered regulations in multiple expected diabetic pathways related to podocyte disruption and hinting at early vascular dysregulation without obvious morphological alterations. Metabolome analysis and pharmacological intervention experiments revealed the contribution of phosphatidylethanolamine in the early establishment of kidney damage. In conclusion, this study identified the pdx1 mutant as a novel model for the study of DKD, showing signs of the early disease progression already in the larval stage and several selective features of later DKD in adult mutants.
PDX1-/- 斑马鱼突变体最近被建立为一种新的糖尿病视网膜病变动物模型。在这项研究中，我们研究了 PDX1 的敲除是否也会导致糖尿病肾病（DKD）。PDX1-/- 幼虫表现出多种早期 DKD 的迹象，如肾小球肥大、滤过屏障损伤导致微量白蛋白尿以及肾小球基底膜（GBM）增厚。与幼虫状态相比，成年 PDX1-/- 突变体显示出进行性 GBM 增厚。杂合子 PDX1 敲除也会导致肾小球肥大，这是 DKD 的初始建立，类似于 PDX1-/- 幼虫。对成年 PDX1+/+肾脏的 RNA 测序揭示了与足细胞破坏相关的多个预期糖尿病途径的调节，并暗示早期血管失调而没有明显的形态改变。代谢组学分析和药理学干预实验揭示了磷脂酰乙醇胺在肾脏损伤早期建立中的作用。总之，本研究确定了 PDX1 突变体作为 DKD 研究的一种新模型，在幼虫阶段就已经显示出疾病进展的早期迹象，并且在成年突变体中还表现出 DKD 后期的一些选择性特征。
