Lupus nephritis is one of the most common and severe complications of systemic lupus erythematosus, of which poor prognosis is indicated by aggravated renal hypoxia and tubulointerstitial fibrosis. Cell adhesion molecules play a key role in the progression of lupus nephritis tubulointerstitial lesion, including P-selectin, which mediates the rolling of leukocytes and subsequent adhesion and infiltration and then initiates the inflammatory immune response and ischemia and hypoxia injury. However, the effects and mechanisms of P-selectin in lupus nephritis remain to be investigated, and a noninvasive measurement of lupus nephritis tubulointerstitial hypoxia and fibrosis remains to be explored. Thirty-four MRL/lpr mice were randomly divided into the following three groups: MRL/lpr, saline, and anti-P-selectin, which consisted of no treatment, treatment with normal saline, and treatment with anti-P-selectin monoclonal antibody (mAb) from 12 to 16 weeks of age, respectively. Ten male C57BL/6 mice of the same age served as normal controls. 24-h urinary protein, urinary albumin–creatinine ratio, and periodic acid–Schiff were used to assess kidney damage; Western blot or immunohistochemical staining of the hypoxia probe Hypoxyprobe™-1, hypoxia-inducible factor 1α (HIF-1α), and CD31 were used to evaluate hypoxia in renal tissue; and NADPH oxidase subunit gp91phox and p22phox were used to examine renal oxidative stress. The correlation between kidney injury and blood oxygen level–dependent magnetic resonance imaging (BOLD-MRI) was calculated to assess the clinical value of BOLD-MRI. P-selectin is upregulated in lupus nephritis. Blocking P-selectin with mAb alleviated renal tubulointerstitial fibrosis, renal hypoxia, and peritubular capillary loss, without alteration of the levels of lupus activity indicators, anti-dsDNA antibody, or complement C3. BOLD-MRI showed that the reduced R2* values in the renal cortex and medulla of lupus mice were increased when treated with anti-P-selectin mAb as compared with those treated with normal saline, which were negatively correlated with Hypoxyprobe™-1 hypoxia probe and the expression of HIF-1α. Early intervention of lupus nephritis with anti-P-selectin mAb can significantly improve the hypoxic state of the kidney and reduce the severity of tubulointerstitial lesions. BOLD-MRI techniques are noninvasive and can dynamically evaluate the changes in renal lesions and intrarenal oxygenation levels before and after treatment in lupus nephritis.

中文翻译：

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P-选择素阻断通过改善肾脏缺氧和 BOLD-MRI 评估来改善 MRL/lpr 小鼠的狼疮肾炎。

狼疮性肾炎是系统性红斑狼疮最常见、最严重的并发症之一，其预后不良，表现为肾脏缺氧加剧和肾小管间质纤维化。细胞粘附分子在狼疮性肾炎肾小管间质病变的进展中发挥着关键作用，其中P-选择素介导白细胞的滚动及随后的粘附和浸润，进而启动炎症免疫反应和缺血缺氧损伤。然而，P-选择素在狼疮性肾炎中的作用和机制仍有待研究，狼疮性肾炎肾小管间质缺氧和纤维化的无创测量仍有待探索。将34只MRL/lpr小鼠随机分为以下三组：MRL/lpr组、生理盐水组、抗P-选择素组，分别为不处理、生理盐水处理、抗P-选择素单克隆抗体处理。 (mAb) 分别从 12 周龄到 16 周龄。10只同龄雄性C57BL/6小鼠作为正常对照。使用24小时尿蛋白、尿白蛋白-肌酐比和高碘酸-希夫来评估肾脏损害；使用缺氧探针 Hypoxyprobe™-1、缺氧诱导因子 1α (HIF-1α) 和 CD31 进行蛋白质印迹或免疫组化染色来评估肾组织缺氧情况；NADPH氧化酶亚基gp91phox和p22phox用于检测肾脏氧化应激。计算肾损伤与血氧水平依赖性磁共振成像（BOLD-MRI）之间的相关性，以评估BOLD-MRI的临床价值。P-选择素在狼疮性肾炎中表达上调。用 mAb 阻断 P-选择素可减轻肾小管间质纤维化、肾缺氧和肾小管周围毛细血管丢失，而不改变狼疮活动指标、抗 dsDNA 抗体或补体 C3 的水平。BOLD-MRI显示，与生理盐水处理相比，使用抗P-选择素单克隆抗体处理狼疮小鼠肾皮质和髓质的R2*值降低增加，且与Hypoxyprobe™-1缺氧探针呈负相关和HIF-1α的表达。采用抗P-选择素单克隆抗体早期干预狼疮性肾炎，可显着改善肾脏缺氧状态，减轻肾小管间质病变的严重程度。BOLD-MRI技术是无创的，可以动态评估狼疮性肾炎治疗前后肾脏病变和肾内氧合水平的变化。