Renal inflammation and injury are associated with lymphangiogenesis in hypertension

Abstract

Lymphatic vessels are vital for the trafficking of immune cells from the interstitium to draining lymph nodes during inflammation. Hypertension is associated with renal infiltration of activated immune cells and inflammation; however, it is unknown how renal lymphatic vessels change in hypertension. We hypothesized that renal macrophage infiltration and inflammation would cause increased lymphatic vessel density in hypertensive rats. Spontaneously hypertensive rats (SHR) that exhibit hypertension and renal injury (SHR-A3 strain) had significantly increased renal lymphatic vessel density and macrophages at 40 wk of age compared with Wistar-Kyoto (WKY) controls. SHR rats that exhibit hypertension but minimal renal injury (SHR-B2 strain) had significantly less renal lymphatic vessel density compared with WKY rats. The signals for lymphangiogenesis, VEGF-C and its receptor VEGF-R3, and proinflammatory cytokine genes increased significantly in the kidneys of SHR-A3 rats but not in SHR-B2 rats. Fischer 344 rats exhibit normal blood pressure but develop renal injury as they age. Kidneys from 24-mo- and/or 20-mo-old Fischer rats had significantly increased lymphatic vessel density, macrophage infiltration, VEGF-C and VEGF-R3 expression, and proinflammatory cytokine gene expression compared with 4-mo-old controls. These data together demonstrate that renal immune cell infiltration and inflammation cause lymphangiogenesis in hypertension- and aging-associated renal injury.

6-Gingerol Normalizes the Expression of Biomarkers Related to Hypertension via PPARδ in HUVECs, HEK293, and Differentiated 3T3-L1 Cells

“…In addition, recent studies strongly suggest the corelation between renal inflammation and hypertension [37, 38]. In this study, the mRNA level of TNF α elevated by NaCl was decreased with 6- gingerol treatment, and the regulation of TNF α by 6-gingerol was PPAR δ -dependent.…”

VEGF‐C attenuates renal damage in salt‐sensitive hypertension

“…On the other hand, in all CKD a prominent accumulation of lymphatic vessels was present in association with MPS cell infiltration in the tubulointerstitium of the cortex. These newly formed lymphatic vessels, that is, de novo lymphangiogenesis, help to manage the increase in interstitial fluid related to inflammation (Kneedler et al, ; A. S. Lee et al, ; Matsui et al, ; Sakamoto et al, ; Seeger, Bonani, & Segerer, ; Suzuki et al, ; Yazdani et al, ). Kidney‐specific augmentation of lymphatic vessels before hypertensive stimuli have been shown to prevent renal immune cell accumulation and prevent the development of hypertension (Lopez Gelston et al, ).…”

“…Most importantly, the prerequisite for the development of these lymphatic vessels is kidney injury independently from the presence of hypertension (Kneedler et al, ). Because high salt damages the kidney (Boero, Pignataro, & Quarello, ; Lambers Heerspink, Navis, & Ritz, ; McMahon, Campbell, Bauer, & Mudge, ; McMahon et al, ; Sanders, ; Saran et al, ; Wright & Cavanaugh, ), as in our study, we postulate that the observed induction of renal lymphangiogenesis is a consequence of salt aggression on renal tissue and not a high blood pressure effect.…”

Lymphatic Vessel Network Structure and Physiology

“…Lastly, in spontaneously hypertensive rats that exhibit hypertension combined with renal injury (SHR-A3 strain), lymphatic vessel density and macrophage infiltration into the kidney were both significantly elevated compared to normotensive Wistar-Kyoto (WKY) background controls (544), suggesting lymphatic network remodeling in response associated with renal diseases. Similar observations were also reported when comparing aged Fischer rats (20–24 months old), along with elevated inflammation and Vegfc/Vegfr3 expression, compared to 4-month old controls (544). Increased lymphatic vessel density has also been observed in mice that have hypertension due to salt sensitivity or inhibition of nitric oxide synthase activity.…”