Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.
Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Nat Commun. 2022 Sep 6;13(1):5253. doi: 10.1038/s41467-022-32972-z.
The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease.
近端小管是调节肾脏功能和葡萄糖代谢的关键。糖尿病肾病导致近端小管损伤和染色质可及性改变，改变参与葡萄糖代谢和炎症的转录因子的活性。在这里，我们使用单核 RNA 和 ATAC 测序表明，糖尿病肾病导致糖皮质激素受体结合位点的可及性降低，并在近端小管中表现出与损伤相关的表达特征。我们假设染色质可及性受遗传背景的调节，并与代谢记忆紧密交织，后者使近端小管对外部刺激产生不同的反应。长期以来，糖皮质激素过多被认为会增加 2 型糖尿病的风险，这增加了糖皮质激素受体抑制可能减轻糖尿病肾病不良代谢影响的可能性。
