Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
Department of Medical Laboratories, Faculty of Health Sciences, American University of Madaba (AUM), Amman, Jordan.
Nat Commun. 2022 Aug 27;13(1):5062. doi: 10.1038/s41467-022-32477-9.
A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, sustained tubular p21 expression in DKD is linked to demethylation of its promoter and reduced DNMT1 expression. Two disease resolving agents, protease activated protein C (3K3A-aPC) and parmodulin-2, reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted.
糖尿病的一个主要障碍是代谢或高血糖记忆，目前缺乏特异性治疗方法。在这里，我们发现，尽管高血糖得到了逆转，但在糖尿病肾病（DKD）中，基因表达的代谢变化仍在很大程度上持续存在。衰老相关的细胞周期蛋白依赖性激酶抑制剂 p21（Cdkn1a）是高血糖诱导的基因中最显著的基因，与 p53-p21 通路的诱导有关。在各种动物模型、人类样本和体外模型中均证实了 p21 的持续诱导。肾小管和尿 p21 水平与 DKD 的严重程度相关，即使在人类血糖水平得到改善的情况下，其水平仍保持升高。从机制上讲，DKD 中持续的肾小管 p21 表达与启动子的去甲基化和 DNMT1 表达减少有关。两种疾病缓解剂，蛋白酶激活蛋白 C（3K3A-aPC）和帕莫杜林-2，可逆转持续的肾小管 p21 表达、肾小管衰老和 DKD。因此，p21 依赖性肾小管衰老是导致高血糖记忆的途径之一，可以作为治疗靶点。
