Department of Urology, Puerta de Hierro-Majadahonda University Hospital, 28222 Majadahonda, Spain.
Department of Medical Specialties and Public Health, King Juan Carlos University, 28933 Madrid, Spain.
Cells. 2022 Jul 27;11(15):2306. doi: 10.3390/cells11152306.
Urolithiasis is a worldwide problem and a risk factor for kidney injury. Oxidative stress-associated renal endothelial dysfunction secondary to urolithiasis could be a key pathogenic factor, similar to obesity and diabetes-related nephropathy. The aim of the present study was to characterize urolithiasis-related endothelial dysfunction in a hyperoxaluria rat model of renal lithiasis.
Endothelial dysfunction was assessed in preglomerular arteries isolated from control rats and in which 0.75% ethylene glycol was administered in drinking water. Renal interlobar arteries were mounted in microvascular myographs for functional studies; superoxide generation was measured by chemiluminescence and mRNA and protein expression by RT-PCR and immunofluorescence, respectively. Selective inhibitors were used to study the influence of the different ROS sources, xanthine oxidase, COX-2, Nox1, Nox2 and Nox4. Inflammatory vascular response was also studied by measuring the RNAm expression of NF-κB, MCP-1 and TNFα by RT-PCR.
Endothelium-dependent vasodilator responses were impaired in the preglomerular arteries of the hyperoxaluric group along with higher superoxide generation in the renal cortex and vascular inflammation developed by MCP-1 and promoted by NF-κB. The xanthine oxidase inhibitor allopurinol restored the endothelial relaxations and returned superoxide generation to basal values. Nox1 and Nox2 mRNA were up-regulated in arteries from the hyperoxaluric group, and Nox1 and Nox2 selective inhibitors also restored the impaired vasodilator responses and normalized NADPH oxidase-dependent higher superoxide values of renal cortex from the hyperoxaluric group.
The current data support that hyperoxaluria induces oxidative stress-mediated endothelial dysfunction and inflammatory response in renal preglomerular arteries which is promoted by the xanthine oxidase, Nox1 and Nox2 pathways.
尿石症是一个全球性的问题，也是肾脏损伤的一个危险因素。与肥胖和糖尿病相关的肾病一样，尿石症引起的氧化应激相关的肾内皮功能障碍可能是一个关键的致病因素。本研究的目的是在草酸钙肾结石大鼠模型中描述与尿石症相关的内皮功能障碍。
评估对照组大鼠和 0.75%乙二醇饮水组大鼠肾小球前动脉的内皮功能障碍。将肾叶间动脉安装在微血管肌动描记器上进行功能研究；通过化学发光法测量超氧化物的产生，通过 RT-PCR 和免疫荧光分别测量 mRNA 和蛋白质表达。使用选择性抑制剂研究不同 ROS 来源、黄嘌呤氧化酶、COX-2、Nox1、Nox2 和 Nox4 的影响。通过 RT-PCR 还研究了炎症性血管反应，测量 NF-κB、MCP-1 和 TNFα 的 RNAm 表达。
高草酸尿组肾小球前动脉的内皮依赖性血管舒张反应受损，同时肾皮质中超氧化物生成增加，血管炎症由 MCP-1 介导，并由 NF-κB 促进。黄嘌呤氧化酶抑制剂别嘌呤醇恢复了内皮松弛，并将超氧化物生成恢复到基础水平。高草酸尿组动脉中 Nox1 和 Nox2 mRNA 上调，Nox1 和 Nox2 选择性抑制剂也恢复了受损的血管舒张反应，并使高草酸尿组肾皮质 NADPH 氧化酶依赖性超氧化物值恢复正常。
目前的数据支持高草酸尿诱导肾小球前动脉氧化应激介导的内皮功能障碍和炎症反应，这是由黄嘌呤氧化酶、Nox1 和 Nox2 途径促进的。
