Department of Diabetes, Central Clinical School, Monash University, 99 Commercial Road, Level 5, Melbourne, VIC, 3004, Australia.
Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Diabetologia. 2019 Sep;62(9):1712-1726. doi: 10.1007/s00125-019-4924-z. Epub 2019 Jun 20.
AIMS/HYPOTHESIS: Excessive production of reactive oxygen species (ROS) plays a detrimental role in the progression of diabetic kidney disease (DKD). Renal oxidative stress activates proinflammatory cytokines, chemokines and profibrotic factors in DKD. Increased expression of the prooxidant enzyme NADPH oxidase (NOX) 5 in kidneys of diabetic individuals has been hypothesised to correlate with renal injury and progression of DKD. Since the gene encoding NOX5 is not expressed in the mouse genome, we examined the effect of inducible human NOX5 expression in renal cells, selectively in either endothelial cells or vascular smooth muscle cells (VSMCs)/mesangial cells in a model of insulin-deficient diabetes, the Akita mouse.
Renal structural injury, including glomerulosclerosis, mesangial expansion and extracellular matrix protein accumulation, as well as renal inflammation, ROS formation and albuminuria, were examined in the NOX5 transgenic Akita mouse model of DKD.
Expression of NOX5 in either endothelial cells or VSMCs/mesangial cells in diabetic Akita mice was associated with increased renal inflammation (monocyte chemoattractant protein-1, NF-κB and toll-like receptor-4) and glomerulosclerosis, as well as upregulation of protein kinase C-α and increased expression of extracellular matrix genes (encoding collagen III, fibronectin and α-smooth muscle actin) and proteins (collagen IV), most likely mediated via enhanced renal ROS production. The effect of VSMC/mesangial cell-specific NOX5 expression resulted in more pronounced renal fibrosis in comparison with endothelial cell-specific NOX5 expression in diabetic mice. In addition, albuminuria was significantly increased in diabetic VEcadNOX5 mice (1192 ± 194 μg/24 h) when compared with diabetic VEcadNOX5 mice (770 ± 98 μg/24 h). Furthermore, the regulatory components of NOX5 activation, including heat shock protein 90 and transient receptor potential cation channel subfamily C member 6, were upregulated only in the presence of both NOX5 and diabetes.
CONCLUSIONS/INTERPRETATION: The findings from this study highlight the importance of NOX5 in promoting diabetes-related renal injury and provide the rationale for the development of a selective NOX5 inhibitor for the prevention and/or treatment of DKD.
目的/假设：活性氧（ROS）的过度产生在糖尿病肾病（DKD）的进展中起着有害的作用。肾脏氧化应激激活糖尿病中的促炎细胞因子、趋化因子和促纤维化因子。已经假设，糖尿病个体肾脏中过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）的表达增加与肾脏损伤和 DKD 的进展相关。由于编码 NOX5 的基因在小鼠基因组中不表达，因此我们在胰岛素缺乏性糖尿病模型（Akita 小鼠）中检查了诱导型人源 NOX5 表达在肾脏细胞（选择性地在血管内皮细胞或血管平滑肌细胞（VSMCs）/系膜细胞中）中的作用。
在 DKD 的 NOX5 转基因 Akita 小鼠模型中，检查了包括肾小球硬化、系膜扩张和细胞外基质蛋白积累在内的肾脏结构损伤，以及肾脏炎症、ROS 形成和白蛋白尿。
在糖尿病 Akita 小鼠中，NOX5 在血管内皮细胞或 VSMCs/系膜细胞中的表达与肾脏炎症（单核细胞趋化蛋白-1、核因子-κB 和 Toll 样受体-4）和肾小球硬化有关，以及蛋白激酶 C-α的上调和细胞外基质基因（编码胶原 III、纤维连接蛋白和α-平滑肌肌动蛋白）和蛋白（胶原 IV）的表达增加，这可能是通过增强肾脏 ROS 产生介导的。与糖尿病小鼠中血管内皮细胞特异性 NOX5 表达相比，VSMCs/系膜细胞特异性 NOX5 表达导致更明显的肾脏纤维化。此外，与糖尿病 VEcadNOX5 小鼠（770±98μg/24h）相比，糖尿病 VEcadNOX5 小鼠的白蛋白尿显着增加（1192±194μg/24h）。此外，仅在存在 NOX5 和糖尿病的情况下，NOX5 激活的调节成分，包括热休克蛋白 90 和瞬时受体电位阳离子通道亚家族 C 成员 6，上调。
结论/解释：本研究的结果强调了 NOX5 在促进糖尿病相关的肾脏损伤中的重要性，并为开发选择性 NOX5 抑制剂用于预防和/或治疗 DKD 提供了依据。
