Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Department of Pathology, Zunyi maternity and Child Healthcare Hospital, Zunyi.
Curr Opin Nephrol Hypertens. 2021 Jan;30(1):115-122. doi: 10.1097/MNH.0000000000000663.
Diabetic kidney disease (DKD) is a leading cause of mortality and morbidity in diabetes. This review aims to discuss the major features of DKD, to identify the difficult barrier encountered in developing a therapeutic strategy and to provide a potentially superior novel approach to retard DKD.
Renal inflammation and fibrosis are prominent features of DKD. Transforming growth factor beta (TGFβ) with its activity enhanced in DKD plays a key pathological profibrotic role in promoting renal fibrosis. However, TGFβ is a difficult drug target because it has multiple important physiological functions, such as immunomodulation. These physiological functions of TGFβ can be interrupted as a result of complete blockade of the TGFβ pathway if TGFβ is directly targeted, leading to catastrophic side-effects, such as fulminant inflammation. Cell division autoantigen 1 (CDA1) is recently identified as an enhancer of profibrotic TGFβ signaling and inhibitor of anti-inflammatory SIRT1. Renal CDA1 expression is elevated in human DKD as well as in rodent models of DKD. Targeting CDA1, by either genetic approach or pharmacological approach in mice, leads to concurrent attenuation of renal fibrosis and inflammation without any deleterious effects observed.
Targeting CDA1, instead of directly targeting TGFβ, represents a superior approach to retard DKD.
糖尿病肾病（DKD）是糖尿病患者死亡和发病的主要原因。本综述旨在讨论 DKD 的主要特征，确定在制定治疗策略时遇到的困难障碍，并提供一种可能更优越的延缓 DKD 的新方法。
肾脏炎症和纤维化是 DKD 的突出特征。转化生长因子β（TGFβ）在 DKD 中活性增强，在促进肾纤维化方面发挥着关键的病理性促纤维化作用。然而，TGFβ 是一个难以成药的靶点，因为它具有多种重要的生理功能，如免疫调节。如果直接针对 TGFβ，阻断 TGFβ 途径可能会中断 TGFβ 的这些生理功能，导致灾难性的副作用，如暴发性炎症。细胞分裂自身抗原 1（CDA1）最近被确定为促纤维化 TGFβ 信号的增强子和抗炎 SIRT1 的抑制剂。在人类 DKD 以及 DKD 的啮齿动物模型中，肾脏 CDA1 的表达升高。在小鼠中，通过基因或药理学方法靶向 CDA1，可同时减轻肾纤维化和炎症，而没有观察到任何不良影响。
靶向 CDA1 而不是直接靶向 TGFβ，是延缓 DKD 的一种更优越的方法。
