Brooke Burgess

Introduction: Hypertension (HTN) is a state of abnormally high blood pressure and is the most common chronic disease world-wide.¹ HTN can lead to significant morbidity over time. Current pharmacological treatments have many side effects and are not effective in 12.8% of the population. Therefore, developing an alternative treatment with less side effects would be extremely useful.² There is an extremely strong association between renal inflammation and salt-sensitive HTN (SSHTN).⁴ Therefore, infiltration of the kidneys by immune cells has been implicated as a possible mechanism causing HTN. Lymphatic density modulates immune cell entry and exit to/from the kidneys, therefore might play an important role in hypertension.³  Franco et al. has shown that there is a direct correlation between increasing blood pressure and increased renal inflammation, including increased levels of IL-6, IL-2, and presence of lymphocytes (CD3+ cells) in the kidney.⁴ Increased immune cell extravasation occurs due to lymphangiogenesis that occurs during inflammation. Inflammation-associated lymphangiogenesis (IAL) is the creation of new lymphatic vessels in the presence of prolonged inflammation.⁵ The primary mechanism by which this occurs is the binding of VEGF-C and VEGF-D to their receptor VEGFR-3.⁵ It is our hypothesis that renal lymphangiogenesis (LAG) might help ameliorate HTN by reducing immune cell accumulation in the kidneys. Further LAG past normal might encourage extravasation of immune cells out of the tissues. Kneedler et al. has shown that spontaneously hypertensive rats exhibited significantly expanded lymphatic network and macrophages compared to the control rats.⁵ This did not occur in rats without renal injury. Methods: Then, Lopez Gelston et al. utilized a genetic approach to cause over expression of renal-specific VEGF-D in response to Doxycycline administration in mice, then induced SSHTN in the experimental group.  Result: The lymphatic network was expanded in the kidneys only, which prevented the development of SSHTN in the mice receiving a high salt diet.³ These mice also showed decreases in inflammatory cytokines and markers of T-Cells and Macrophages.³ Conclusions: These findings were confirmed by Beaini et al. in 2019 by administration of VEGF-C to mice both with and without a high salt diet. This resulted in decreased inflammatory cytokines and decreased fibrosis and systolic blood pressure in hypertensive mice.⁶ Both of these studies show that an expanded lymphatic network serves to ameliorate renal inflammation and hypertension. Targeted renal lymphangiogenesis might be a promising therapeutic modality for humans in the future. Delineating a way to increase renal-specific VEGF-C/D in humans could completely change the way HTN is treated in the general population for the better.

1. Norlander AE, Madjur MS, Harrison DG. The immunology of hypertension. JEM.  2019;215(1):21-33.
2. Balasubbramanian D, Lopez Gelston CA, Rutkowski JM, Mitchell BM. Immune cell trafficking, lymphatics and hypertension. Br J Pharamacol. 2018. DOI: 10.1111/bph.14370.
3. Lopez Gelston CA and Mitchell BM. Recent advances in immunity and hypertension. Am J Hypertens. 2017;30(7):643-652.
4. Franco M, et al. Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney. Am J Physiol Renal Physiol. 2013;304(7):F982-F990.
5. Kneedler SC, et al. Renal inflammation and injury are associated with lymphangiogenesis in hypertension. Am J Physiol Renal Physiol. 2017;312:F861-F869.
6. Beaini S, et al. VEGF-C attenuates renal damage in salt-sensitive hypertension. J Cell Physiol. 2018; https://doi.org/10.1002/jcp.27648