Genetically inducing renal lymphangiogenesis attenuates hypertension in mice
Open Access
- 2 December 2022
- journal article
- Published by Portland Press Ltd. in Clinical Science
- Vol. 136 (23), 1759-1772
- https://doi.org/10.1042/cs20220547
Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: These findings demonstrate that augmenting renal lymphangiogenesis can treat HTN in male and female mice by improving renal immune cell trafficking and sodium handling.Keywords
This publication has 49 references indexed in Scilit:
- Altered Dynamics in the Renal Lymphatic Circulation of Type 1 and Type 2 Diabetic MiceACTA HISTOCHEMICA ET CYTOCHEMICA, 2013
- Sodium, Blood Pressure, and Cardiovascular DiseaseJournal of the American College of Cardiology, 2012
- Mice lacking macrophage 12/15-lipoxygenase are resistant to experimental hypertensionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2012
- Lymph node–resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentationThe Journal of Experimental Medicine, 2010
- Role of Inflammation in the Development of Renal Damage and Dysfunction in Angiotensin II–Induced HypertensionHypertension, 2008
- Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunctionThe Journal of Experimental Medicine, 2007
- Increased lymphangiogenesis in joints of mice with inflammatory arthritisArthritis Research & Therapy, 2007
- Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusionsAmerican Journal of Physiology-Renal Physiology, 2007
- Recommendations for Blood Pressure Measurement in AnimalsArteriosclerosis, Thrombosis, and Vascular Biology, 2005
- Comparison of simultaneous measurement of mouse systolic arterial blood pressure by radiotelemetry and tail-cuff methodsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2004