Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama.
Am J Physiol Renal Physiol. 2021 Dec 1;321(6):F675-F688. doi: 10.1152/ajprenal.00186.2021. Epub 2021 Oct 18.
Expansion of renal lymphatic networks, or lymphangiogenesis (LA), is well recognized during development and is now being implicated in kidney diseases. Although LA is associated with multiple pathological conditions, very little is known about its role in acute kidney injury. The purpose of this study was to evaluate the role of LA in a model of cisplatin-induced nephrotoxicity. LA is predominately regulated by vascular endothelial growth factor (VEGF)-C and VEGF-D, ligands that exert their function through their cognate receptor VEGF receptor 3 (VEGFR3). We demonstrated that use of MAZ51, a selective VEGFR3 inhibitor, caused significantly worse structural and functional kidney damage in cisplatin nephrotoxicity. Apoptotic cell death and inflammation were also increased in MAZ51-treated animals compared with vehicle-treated animals following cisplatin administration. Notably, MAZ51 caused significant upregulation of intrarenal phospho-NF-κB, phospho-JNK, and IL-6. Cisplatin nephrotoxicity is associated with vascular congestion due to endothelial dysfunction. Using three-dimensional tissue cytometry, a novel approach to explore lymphatics in the kidney, we detected significant vascular autofluorescence attributed to erythrocytes in cisplatin alone-treated animals. Interestingly, no such congestion was detected in MAZ51-treated animals. We found increased renal vascular damage in MAZ51-treated animals, whereby MAZ51 caused a modest decrease in the endothelial markers endomucin and von Willebrand factor, with a modest increase in VEGFR2. Our findings identify a protective role for de novo LA in cisplatin nephrotoxicity and provide a rationale for the development of therapeutic approaches targeting LA. Our study also suggests off-target effects of MAZ51 on the vasculature in the setting of cisplatin nephrotoxicity. Little is known about injury-associated LA in the kidney and its role in the pathophysiology of acute kidney injury (AKI). Observed exacerbation of cisplatin-induced AKI after LA inhibition was accompanied by increased medullary damage and cell death in the kidney. LA inhibition also upregulated compensatory expression of LA regulatory proteins, including JNK and NF-κB. These data support the premise that LA is induced during AKI and lymphatic expansion is a protective mechanism in cisplatin nephrotoxicity.
肾脏淋巴管网络的扩张，即淋巴管生成（LA），在发育过程中得到了很好的认识，现在它与肾脏疾病有关。尽管 LA 与多种病理状况有关，但人们对其在急性肾损伤中的作用知之甚少。本研究旨在评估 LA 在顺铂诱导的肾毒性模型中的作用。LA 主要受血管内皮生长因子（VEGF）-C 和 VEGF-D 的调节，这些配体通过其同源受体血管内皮生长因子受体 3（VEGFR3）发挥作用。我们证明，使用选择性 VEGFR3 抑制剂 MAZ51，会导致顺铂肾毒性中结构和功能更严重的肾脏损伤。与顺铂给药后给予载体的动物相比，MAZ51 处理的动物的凋亡细胞死亡和炎症也增加。值得注意的是，MAZ51 导致肾内磷酸化 NF-κB、磷酸化 JNK 和 IL-6 的显著上调。顺铂肾毒性与内皮功能障碍引起的血管充血有关。使用三维组织细胞计量术，这是一种探索肾脏淋巴管的新方法，我们检测到顺铂单独处理的动物中存在显著的血管自发荧光，这归因于红细胞。有趣的是，在 MAZ51 处理的动物中没有检测到这种充血。我们发现 MAZ51 处理的动物的肾脏血管损伤增加，MAZ51 导致内皮标志物内粘蛋白和血管性血友病因子略有减少，而 VEGFR2 略有增加。我们的发现确定了新生成的 LA 在顺铂肾毒性中的保护作用，并为针对 LA 的治疗方法的开发提供了依据。我们的研究还表明，MAZ51 在顺铂肾毒性中对血管存在脱靶效应。关于肾脏中与损伤相关的 LA 及其在急性肾损伤（AKI）病理生理学中的作用知之甚少。在 LA 抑制后观察到顺铂诱导的 AKI 加重，同时肾脏的髓质损伤和细胞死亡增加。LA 抑制还上调了 LA 调节蛋白，包括 JNK 和 NF-κB 的代偿性表达。这些数据支持 LA 在 AKI 期间被诱导的前提，并且淋巴管扩张是顺铂肾毒性中的一种保护机制。
