Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A.
Clin Sci (Lond). 2022 Dec 9;136(23):1759-1772. doi: 10.1042/CS20220547.
Hypertension (HTN) is associated with renal proinflammatory immune cell infiltration and increased sodium retention. We reported previously that renal lymphatic vessels, which are responsible for trafficking immune cells from the interstitial space to draining lymph nodes, increase in density under hypertensive conditions. We also demonstrated that augmenting renal lymphatic density can prevent HTN in mice. Whether renal lymphangiogenesis can treat HTN in mice is unknown. We hypothesized that genetically inducing renal lymphangiogenesis after the establishment of HTN would attenuate HTN in male and female mice from three different HTN models.
Mice with inducible kidney-specific overexpression of VEGF-D (KidVD) experience renal lymphangiogenesis upon doxycycline administration. HTN was induced in KidVD+ and KidVD- mice by subcutaneous release of angiotensin II, administration of the nitric oxide synthase inhibitor L-NAME, or consumption of a 4% salt diet following a L-NAME priming and washout period. After a week of HTN stimuli treatment, doxycycline was introduced. Systolic blood pressure (SBP) readings were taken weekly. Kidney function was determined from urine and serum measures. Kidneys were processed for RT-qPCR, flow cytometry, and imaging.
Mice that underwent renal-specific lymphangiogenesis had significantly decreased SBP and renal proinflammatory immune cells. Additionally, renal lymphangiogenesis was associated with a decrease in sodium transporter expression and increased fractional excretion of sodium, indicating improved sodium handling efficiency.
These findings demonstrate that augmenting renal lymphangiogenesis can treat HTN in male and female mice by improving renal immune cell trafficking and sodium handling.
高血压（HTN）与肾脏促炎免疫细胞浸润和钠潴留增加有关。我们之前曾报道过，在高血压条件下，负责将免疫细胞从间质空间运送到引流淋巴结的肾脏淋巴管密度增加。我们还证明，增加肾脏淋巴管密度可以预防小鼠的 HTN。然而，肾脏淋巴管生成是否可以治疗 HTN 尚不清楚。我们假设，在 HTN 确立后，通过遗传诱导肾脏淋巴管生成，将减轻来自三种不同 HTN 模型的雄性和雌性小鼠的 HTN。
在给予强力霉素后，具有诱导性肾脏特异性过表达 VEGF-D（KidVD）的小鼠会经历肾脏淋巴管生成。KidVD+和 KidVD-小鼠通过皮下释放血管紧张素 II、给予一氧化氮合酶抑制剂 L-NAME 或在 L-NAME 引发和冲洗期后消耗 4%盐饮食来诱导 HTN。在 HTN 刺激治疗一周后，引入强力霉素。每周测量收缩压（SBP）读数。通过尿液和血清测量来确定肾功能。对肾脏进行 RT-qPCR、流式细胞术和成像处理。
进行肾脏特异性淋巴管生成的小鼠的 SBP 和肾脏促炎免疫细胞显著降低。此外，肾脏淋巴管生成与钠转运体表达减少和钠排泄分数增加有关，表明钠处理效率提高。
这些发现表明，通过改善肾脏免疫细胞转运和钠处理，增加肾脏淋巴管生成可以治疗雄性和雌性小鼠的 HTN。
