Petrazzuolo Adriana, Sabiu Gianmarco, Assi Emma, Maestroni Anna, Pastore Ida, Lunati Maria Elena, Montefusco Laura, Loretelli Cristian, Rossi Giada, Ben Nasr Moufida, Usuelli Vera, Xie Yanan, Balasubramanian Hari Baskar, Zocchi Monica, El Essawy Basset, Yang Jun, D'Addio Francesca, Fiorina Paolo
International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università degli Studi di Milano, Milan, Italy.
International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università degli Studi di Milano, Milan, Italy; Boston Children's Hospital and Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Pharmacol Res. 2023 Apr;190:106710. doi: 10.1016/j.phrs.2023.106710. Epub 2023 Mar 4.
Diabetic kidney disease (DKD) is the first cause of end-stage kidney disease in patients with diabetes and its prevalence is increasing worldwide. It encompasses histological alterations that mainly affect the glomerular filtration unit, which include thickening of the basement membrane, mesangial cell proliferation, endothelial alteration, and podocyte injury. These morphological abnormalities further result in a persistent increase of urinary albumin-to-creatinine ratio and in a reduction of the estimated glomerular filtration rate. Several molecular and cellular mechanisms have been recognized, up to date, as major players in mediating such clinical and histological features and many more are being under investigation. This review summarizes the most recent advances in understanding cell death mechanisms, intracellular signaling pathways and molecular effectors that play a role in the onset and progression of diabetic kidney damage. Some of those molecular and cellular mechanisms have been already successfully targeted in preclinical models of DKD and, in some cases, strategies have been tested in clinical trials. Finally, this report sheds light on the relevance of novel pathways that may become therapeutic targets for future applications in DKD.
糖尿病肾病（DKD）是糖尿病患者终末期肾病的首要病因，其在全球范围内的患病率正在上升。它包括主要影响肾小球滤过单位的组织学改变，这些改变包括基底膜增厚、系膜细胞增殖、内皮改变和足细胞损伤。这些形态学异常进一步导致尿白蛋白与肌酐比值持续升高以及估计肾小球滤过率降低。迄今为止，几种分子和细胞机制已被确认为介导此类临床和组织学特征的主要因素，还有更多机制正在研究中。本综述总结了在理解细胞死亡机制、细胞内信号通路和分子效应器方面的最新进展，这些在糖尿病肾损伤的发生和发展中发挥作用。其中一些分子和细胞机制已在DKD临床前模型中成功靶向，在某些情况下，相关策略已在临床试验中进行了测试。最后，本报告阐明了可能成为DKD未来治疗靶点的新途径的相关性。
