Genetically inducing renal lymphangiogenesis attenuates hypertension in mice

Abstract

Background: Hypertension (HTN) is associated with renal pro-inflammatory 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 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 systolic blood pressure and renal pro-inflammatory 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.

Skin sodium, lymphatics, and blood pressure: a non-canonical mechanism of salt-sensitive hypertension

“…This attenuation of HTN is accompanied by decreased proinflammatory renal immune cell accumulation, potentially via enhanced trafficking from the tissue. 15 Additionally, Zhuang et al, in the current study, observed an increase in dermal lymphatic capillary density rather than their hypoplastic response to HSD in wild-type animals, which contradicts data found in humans. This suggests that further research is needed, and better-refined models or longer salt treatments that better recapitulate human SSHTN development must be used.…”

Novel avenues to control blood pressure: targeting the renal lymphatic system

“…The work published by Goodlett and collaborators in Clinical Science [ 18 ] complements previous work from the same group where they have observed that when renal lymphangiogenesis is genetically induced, KidVD+ mice fail to develop hypertension when challenged with A2HTN [ 14 ], LHTN [ 13 ], and SSHTN [ 13 ] models of hypertension. In the present study, they demonstrate that the reduction in blood pressure in all three models of hypertension seem to share a basic mechanism adaptation to increase sodium clearance as shown by an increase in the fractional excretion of sodium (FENa) that is associated with the decrease expression of the sodium transporters NCC (sodium-chloride symporter), Nhe3 (sodium-hydrogen exchanger 3), and ENaC (epithelium sodium channel) in the A2HTN and SSHTN models of hypertension but not in the LHTN model of hypertension.…”

“…The findings of Goodlett and colleagues [ 18 ] recently published in Clinical Science advance the field by showing evidence that the genetic induction of renal lymphangiogenesis after the establishment of hypertension is an efficient approach to restore normal blood pressure levels in mice. The study elegantly used three different models of hypertension induced either by angiotensin II (A2HTN), the inhibition of endothelial nitric oxide synthase (eNOS) (LHTN) or the inhibition of eNOS followed by a washout period and the addition of 4% salt to the diet (SSHTN).…”