McCurley Amy, Alimperti Stella, Campos-Bilderback Silvia B, Sandoval Ruben M, Calvino Jenna E, Reynolds Taylor L, Quigley Catherine, Mugford Joshua W, Polacheck William J, Gomez Ivan G, Dovey Jennifer, Marsh Graham, Huang Angela, Qian Fang, Weinreb Paul H, Dolinski Brian M, Moore Shaun, Duffield Jeremy S, Chen Christopher S, Molitoris Bruce A, Violette Shelia M, Crackower Michael A
Biogen Inc., Cambridge, Massachusetts;
Department of Biomedical Engineering, Boston University, Boston, Massachusetts.
J Am Soc Nephrol. 2017 Jun;28(6):1741-1752. doi: 10.1681/ASN.2016020200. Epub 2017 Jan 6.
Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The v5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit v5 in a rat model of renal IRI. Pretreatment with this anti-v5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the v5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that v5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with v5 antibody treatment. Immunostaining for v5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for v5 in modulating vascular leak. Additional studies showed v5 functions in the adhesion and migration of kidney pericytes Initial studies monitoring renal blood flow after IRI did not find significant effects with v5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for v5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal v5 inhibition as a promising therapeutic strategy for AKI.
缺血再灌注损伤（IRI）是急性肾损伤（AKI）的主要原因。这种常见的临床并发症缺乏有效的治疗方法，可导致慢性肾脏病（CKD）的发生。v5整合素可能在急性损伤中起重要作用，包括脓毒性休克和急性肺损伤。为了研究其在AKI中的功能，我们在大鼠肾IRI模型中使用特异性功能阻断抗体抑制v5。用这种抗v5抗体预处理可显著降低血清肌酐水平，减轻组织病理学评估检测到的肾损伤，并降低损伤生物标志物的水平。值得注意的是，IRI后8小时用v5抗体进行治疗也能提供损伤保护。缺血后肾脏的全基因组表达谱分析表明，v5抑制影响已确定的损伤标志物，并诱导先前显示具有保护作用的信号通路改变。缺血后肾脏的活体成像显示，v5抗体治疗可减少血管渗漏。肾脏中v5的免疫染色检测到血管周围细胞中有明显表达，而在内皮细胞中表达可忽略不计。在三维微流控系统中的研究确定了v5在调节血管渗漏中依赖周细胞的作用。进一步的研究表明v5在肾周细胞的黏附和迁移中发挥作用。最初监测IRI后肾血流量的研究未发现v5抑制有显著影响；然而，未来的研究应探索血管舒缩效应的作用。这些研究确定了v5在调节损伤诱导的肾血管渗漏中的作用，可能是通过对周细胞黏附和迁移的影响，并揭示v5抑制是一种有前景的AKI治疗策略。
