Nephrology Department, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
Pathology Department, Hospital del Mar, Barcelona, Spain.
Lab Invest. 2020 Sep;100(9):1169-1183. doi: 10.1038/s41374-020-0440-5. Epub 2020 May 29.
Type 1 diabetes is a T-cell mediated autoimmune disease characterized by pancreatic beta cells destruction. Angiotensin-converting enzyme 2 (ACE2), a component of renin-angiotensin system (RAS) has been identified in pancreas from type 2 diabetic mice and its overexpression prevents beta cell dysfunction. We studied the effect of ACE2 deletion on pancreatic and renal function in the nonobese diabetic mice, a model that mimics type 1 diabetes. ACE2-deficient NOD mice and the respective controls were generated. Pancreas function and immunohistochemistry studies were performed. Renal function and RAS gene expression were also analyzed. Renal proximal tubular cells were obtained from these animals to dissect the effect of ACE2 deficiency in these cells. In NOD mice, ACE2 deletion significantly worsened glucose homeostasis, decreased islet insulin content, increased beta cell oxidative stress, and RIPK1-positive islets as compared with control mice. Angiotensin-converting enzyme and angiotensin II type 1 receptor (AT1R) were also increased in ACE2-deficient mice. In kidneys of 30-day diabetic mice, ACE2 deletion decreased podocyte number within the glomeruli, and altered renal RAS gene expression in tubules. ACE2 deletion influenced the expression of fibrosis-related genes in isolated primary renal proximal tubular cells before diabetes onset in NOD mice. Our findings suggest that ACE2 deletion may have a deleterious impact on beta cell and renal function, by promoting oxidative stress and increasing necroptosis mediators. In addition, this effect is accompanied by RAS alterations in both pancreas and renal proximal tubular cells, indicating that ACE2 may exert a renopancreatic protective effect on type 1 diabetes, which is activated before diabetes starts.
1 型糖尿病是一种以胰腺β细胞破坏为特征的 T 细胞介导的自身免疫性疾病。血管紧张素转换酶 2（ACE2）是肾素-血管紧张素系统（RAS）的一个组成部分，已在 2 型糖尿病小鼠的胰腺中被鉴定出来，其过表达可防止β细胞功能障碍。我们研究了 ACE2 缺失对非肥胖型糖尿病小鼠（一种模拟 1 型糖尿病的模型）胰腺和肾脏功能的影响。生成了 ACE2 缺陷型 NOD 小鼠及其相应的对照。进行了胰腺功能和免疫组织化学研究。还分析了肾脏功能和 RAS 基因表达。从这些动物中分离出肾近端管状细胞，以剖析 ACE2 缺乏对这些细胞的影响。在 NOD 小鼠中，与对照组相比，ACE2 缺失显著恶化了葡萄糖稳态，降低了胰岛胰岛素含量，增加了β细胞氧化应激和 RIPK1 阳性胰岛。ACE2 缺陷型小鼠中的血管紧张素转换酶和血管紧张素 II 型 1 型受体（AT1R）也增加了。在 30 天糖尿病小鼠的肾脏中，ACE2 缺失减少了肾小球内足细胞的数量，并改变了肾小管中的肾脏 RAS 基因表达。在 NOD 小鼠糖尿病发病前，ACE2 缺失影响了分离的原发性肾近端管状细胞中纤维化相关基因的表达。我们的研究结果表明，ACE2 缺失可能通过促进氧化应激和增加坏死性凋亡介质对β细胞和肾脏功能产生有害影响。此外，这种影响伴随着胰腺和肾近端管状细胞中 RAS 的改变，表明 ACE2 可能对 1 型糖尿病具有肾胰腺保护作用，这种作用在糖尿病开始前就已经被激活。
