功能性磁共振成像在评估狼疮肾炎小鼠肾脏缺氧损伤中的作用

Role of functional magnetic resonance imaging in evaluating renal hypoxic injury in mice with lupus nephritis

目的通过狼疮肾炎（LN）小鼠模型，探讨功能性磁共振成像（MRI）在评估肾功能损害、肾脏病理改变及肾内缺氧状态中的作用。方法自发性LN模型MRL/lpr小鼠13只，对照组C57BL／6小鼠10只，检测尿白蛋白／肌酐比值（ACR）、血肌酐（Scr）、抗ds．DNA抗体和补体c3水平；14-16周龄小鼠处死前进行肾脏横断面T1加权像（T1WI）、T2加权像（T2WI）、扩散加权成像（DWI）及血氧水平依赖法（BOLD）成像。处死前1h腹腔注射缺氧探针，采用免疫组化、Western印迹法检测小鼠肾组织中缺氧探针（Hypoxyprobe^TM-1）、缺氧诱导因子1饯（HIF—1α）和血红素加氧酶1（HO-1）的分布。结果MRL／lpr小鼠的尿ACR、Scr和抗ds—DNA抗体水平均显著高于对照组，LN模型小鼠肾组织中Hypoxyprobe^TM-1、HIF-1α和HO-1广泛分布，且在肾髓质的小管间质呈弥漫分布，并与肾小管间质病变密切相关。肾脏功能MRI示LN组平均表观扩散系数（ADC）为（1．52±0．27）×10-3 mm2／s，皮质和髓质R2＊值分别为（30．95±4．59）／s和（23．43±3．06）/s，均低于对照组（P分别为0．037、0．030、0．043）。当b=500s／mm2和800s／mm2时，髓质ADC值与尿ACR呈负相关（r=-0．364，P=0．032；r=0．329，P=0．050），皮质ADC值与血肌酐亦呈负相关（r=-0．814，P=0．014；r=-0．755，P=0．031），平均R2＊值与尿ACR、肾小管间质病变程度及肾组织缺氧指标表达均呈负相关（均P〈0．05）。结论肾内缺氧可能在LN肾小管间质病变发生中具有重要作用。无创性的功能性MRI可监测LN小鼠的肾功能变化、肾脏病理改变及肾内缺氧情况。

Objective To investigate the utility of diffusion weighted imaging （DWI） and blood oxygen level-dependent （BOLD） magnetic resonance imaging （MRI） in the assessment of renal hypoxia in an experimental model of mice with lupus nephritis （LN）. Methods MRL/lpr mice （n= 13） were studied and C57BL/6 mice （n=10） served as controls. Urinary albumin to creatinine ratio （ACR）, serum creatinine （Scr）, anti-ds-DNA antibody, and complement C3 levels were measured. The mice underwent coronal echo-planar DWI and BOLD MRI of the kidneys when they were 14-16 weeks old. Hypoxyprobe was administered intraperitoneally to the mice 1 hour before they were sacrificed.The distribution of HypoxyprobeTM-1, hypoxia-inducible factor 1α（HIF-1α） and heme oxygenase-1 （HO-1） in renal tissues was detected by immunohistochemical analysis and Western blotting. Results Urinary ACR, Scr and anti-ds-DNA antibody levels in MRL/lpr mice were significantly higher than that in C57BL/6 mice. It was found that HypoxyprobeTM-1, HIF-1α and HO-1 distributed widely in the renal tissue of MRL/lpr mice, and closely associated with the renal tubulointerstitial lesion. The mean apparent diffusion coefficient （ADC） value of kidneys in MRL/lpr mice was （1.52±0.27）×10-3 mm2/s, and the mean R2＊ values of the renal cortex and medulla were （30.95±4.59）/s and （23.43 ±3.06）/s respectively, all significantly lower than that in C57BL/6 mice （P=0.037, P=0.030 and P=0.043, respectively）. The ADC of medulla was negatively correlated with urinary albumin to creatinine ratio （r=-0.364, P=0.032; r=-0.329, P=0.050）, the ADC of cortex was negatively correlated with the level of serum creatinine （r=-0.814, P=0.014; r=-0.755, P=0.031） when b value was 500 s/mm2 and 800 s/mm2, and the mean R2＊ value was negatively correlated with the degree of tubulointerstitial lesions and the expression of hypoxia parameters （all P 〈 0.05）. Conclusions Renal hypoxia may play an important role in renal tubulointerstitial lesion. Functional MRI may be used to monitor renal function changes, pathological injuries and renal hypoxia in LN.