Lymphatic abnormalities are observed in several types of kidney disease, but the relationship between the renal lymphatic system and renal function is unclear. The discovery of lymphatic-specific proteins, advances in microscopy, and available genetic mouse models provide the tools to help elucidate the role of renal lymphatics in physiology and disease.

We utilized a mouse model containing a missense mutation in Vegfr3 (dubbed Chy) that abrogates its kinase ability. Vegfr3^Chy/+ mice were examined for developmental abnormalities and kidney-specific outcomes. Control and Vegfr3^Chy/+ mice were subjected to cisplatin-mediated injury. We characterized renal lymphatics using tissue-clearing, light-sheet microscopy, and computational analyses.

In the kidney, VEGFR3 is expressed not only in lymphatic vessels but also, in various blood capillaries. Vegfr3^Chy/+ mice had severely reduced renal lymphatics with 100% penetrance, but we found no abnormalities in BP, serum creatinine, BUN, albuminuria, and histology. There was no difference in the degree of renal injury after low-dose cisplatin (5 mg/kg), although Vegfr3^Chy/+ mice developed perivascular inflammation. Cisplatin-treated controls had no difference in total cortical lymphatic volume and length but showed increased lymphatic density due to decreased cortical volume.

We demonstrate that VEGFR3 is required for development of renal lymphatics. Our studies reveal that reduced lymphatic density does not impair renal function at baseline and induces only modest histologic changes after mild injury. We introduce a novel quantification method to evaluate renal lymphatics in 3D and demonstrate that accurate measurement of lymphatic density in CKD requires assessment of changes to cortical volume.

在几种类型的肾脏疾病中观察到淋巴系统异常，但肾淋巴系统与肾功能之间的关系尚不清楚。淋巴管特异性蛋白质的发现、显微镜技术的进步和可用的遗传小鼠模型提供了工具来帮助阐明肾淋巴管在生理学和疾病中的作用。

我们使用了一个小鼠模型，该模型在Vegfr3（称为Chy ）中包含一个错义突变，可消除其激酶能力。检查Vegfr3 ^{Chy/+小鼠的发育异常和肾脏特异性结果。}对照和Vegfr3 ^Chy/+小鼠受到顺铂介导的损伤。我们使用组织透明化、光片显微镜和计算分析来表征肾淋巴管。

在肾脏中，VEGFR3 不仅在淋巴管中表达，而且在各种毛细血管中表达。Vegfr3 ^Chy/+小鼠的肾淋巴管严重减少，外显率为 100%，但我们未发现血压、血清肌酐、BUN、白蛋白尿和组织学异常。低剂量顺铂 (5 mg/kg) 后肾损伤程度没有差异，尽管Vegfr3 ^Chy/+小鼠出现血管周围炎症。顺铂治疗的对照组在总皮质淋巴管体积和长度上没有差异，但由于皮质体积减少，淋巴管密度增加。

我们证明 VEGFR3 是肾淋巴管发育所必需的。我们的研究表明，淋巴管密度降低不会损害基线时的肾功能，并且在轻度损伤后只会引起适度的组织学变化。我们引入了一种新的量化方法来评估 3D 中的肾淋巴管，并证明准确测量 CKD 中的淋巴管密度需要评估皮质体积的变化。