Sodium sensing in the interstitium and relationship to hypertension. - Semantic Scholar
American Journal of Hypertension, Volume 21, Issue 7, 1 July , Pages However, thiazide decreased interstitial fluid calcium in DS on a normal salt diet. .. to be answered is what is the relationship between ISF and blood pressure, if any. Dietary Ca(2+) and blood pressure: evidence that Ca(2+)-sensing receptor. These recruited macrophages sense the interstitial electrolyte composition and .. Sodium sensing in the interstitium and relationship to hypertension. Curr. Data detailed in 'Sodium sensing in the interstitium and relationship to hypertension' have been presented. According to recent research from Germany, “Internal.
Cortical interstitial fluid calcium was unchanged by dietary salt in DR rats, and thiazide did not alter this interstitial fluid calcium response. Conclusion We interpret these data to mean that i short-term thiazide treatment does not reduce blood pressure by restoring renal cortical interstitial fluid calcium concentration and ii a decrease in renal cortical interstitial fluid calcium may not contribute to the increased renal vasoconstriction seen in salt-sensitivity.
When coupled with the vasodilatory action of increased extracellular calcium, 23 these findings suggest that a high salt diet may modulate blood pressure secondary to a disruption in a calcium-dependent vasodilatory effect normally occurring in the cortical region of the kidney.
Thiazides have been shown to be quite effective in lowering blood pressure, particularly within the African-American population. In light of the potential for alterations in extracellular calcium modulation of vascular resistance, 23 the excretion of calcium may be extremely important in the pathogenesis of hypertension development.
Of interest is the finding that thiazides, in addition to increasing urinary sodium loss, significantly reduce urinary calcium excretion.
Methods Animals and treatments study protocol. All animals were housed in separate ventilated cages Animal Care Systems, Littleton, CO maintained at constant temperature and humidity. During acclimation animals were maintained on regular chow Harlan Teklad Laboratories, Madison, WI and water for a period of 7—10 days. Following acclimation, the animals were placed in one of four treatment groups: The previous day's water consumption was used for estimating the HCTZ dosing.
It has been shown that macrophages play an important role in both processes, as angiogenic, and arteriogenic accessory cells Pollard, ; Murdoch et al. Myeloid cells are first attracted to the site of injury, for example by the chemokine CCL2 Low-Marchelli et al. Accordingly, interference with local monocyte attraction to ischemic tissue resulted in flap necrosis due to impaired flap revascularization Khan et al.
Once at the ischemic site, macrophages are exposed to vessel- and tissue-derived cytokines [such as Angiopoietin ANG 1, ANG2, vascular endothelial growth factor A VEGF ], which reprogram them to become highly angiogenic and arteriogenic accessory cells Avraham-Davidi et al. The expression and composition of these vessel- and tissue-derived cytokines are tightly regulated at the ischemic site, and may critically affect the angiogenic and arteriogenic function of macrophages Folkman, ; Saharinen et al.
In addition, local tissue hypoxia and endothelial cell derived signals might maintain this regulatory circuit by promoting TIE2 expression Lewis et al. In many different models of angiogenesis, M2-like alternatively activated macrophages supported the proliferation and migration of endothelial cells and vessel sprouting Jetten et al. This was shown to be as a result of a blockade of the tissue inhibitor of metalloproteinase 1 TIMP1 gene expression, that promotes the secretion of highly angiogenic matrix metalloproteinase MMP 9, which in turn results in the release of matrix-sequestered angiogenic growth factors such as VEGF and FGF-2 from the tissue Zajac et al.
In addition to the above described proangiogenic role of ILdependent M2-like macrophages Zajac et al. In this context, ANG2-dependent TIE2-signaling in macrophages was also found to promote angiogenesis in models of inflammation and cancer Coffelt et al.
Additionally, hypoxia was found to enhance ANG2 expression in murine and human macrophages, which may subsequently boost their proangiogenic function Fang et al. These data demonstrate that macrophage cell function is critically involved in angio- and arteriogenesis Figure 1. Given the role of T cell-derived cytokines on macrophage polarization and activation it is obvious that alteration in T cell activation will also affect angiogenesis and arteriogenesis, and will thus bring another level of complexity to the effect of immune cells on vascular biology Starnes et al.
Macrophages as angiogenic and arteriogenic accessory cells. Macrophages are attracted to ischemic sites where they are transformed into potent angiogenic and arteriogenic accessory cells by tissue- and T cell-derived signals. Macrophages as Glucose and Lipid Sensors Whilst cytokines and chemokines are the main drivers of the activation and function of macrophages, recent studies have revealed that macrophages also respond to environmental cues in the form of small metabolites such as glucose, lipids, and sodium chloride to be discussed further in the following section.
These small metabolites also influence programming of macrophages into either classical or alternative subsets, and can thus modulate macrophage function. Macrophages infiltrate and reside in nearly every tissue, including adipose. Accompanied with the observation that macrophages accumulate within adipose tissue with obesity Weisberg et al.
This process is not subject to a negative feedback mechanism and as such, where there is excess lipid present macrophages can become loaded with lipid and form pro-atherogenic foam cells Nagy et al. In cases of overnutrition, where the adipose tissue is overwhelmed with nutrients resulting in various amounts of cellular stress reviewed by Odegaard and Chawla,macrophages accumulate within adipose tissue and subsequently switch from an alternative activated M2 phenotype to a classically activated M1suggesting that excess fat can enhance the activation of inflammatory signaling pathways Lumeng et al.
This has also been demonstrated by in vitro experiments, where incubation of macrophage with free fatty acids led to the activation of Toll-like receptor 4 signaling, NF-kB activation and subsequently fatty acid-induced insulin resistance Shi et al.
The JNK signaling pathway has additionally been shown to be involved in the activation of inflammatory M1 macrophages and the development of obesity and insulin-resistance Han et al. This was also shown by the deletion of JNK1 in hematopoietic-derived cells, which subsequently resulted in protection against diet-induced inflammation and insulin resistance without affecting obesity Solinas et al.
Sodium sensing in the interstitium and relationship to hypertension.
Under normal conditions, the transcriptional effect of the uptake of lipids by macrophages is the activation of peroxisome proliferator activator receptors PPAR Ricote et al. Find articles by Wu, J. Find articles by Xiao, L. Find articles by Kang, J. Find articles by Dale, B. Find articles by Goleva, S. Find articles by Laroumanie, F.
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Find articles by Harrison, D. Find articles by Madhur, M. January 11, ; Accepted: Thus, we tested the hypothesis that SGK1 signaling in T cells promotes hypertension and contributes to end-organ damage. Importantly, renal and vascular inflammation is abrogated in these mice compared with control mice. These studies demonstrate that T cell SGK1 and NKCC1 may be novel therapeutic targets for the treatment of hypertension and identify a potentially new mechanism by which salt contributes to hypertension.
Introduction Hypertension is a leading cause of death and disability from cardiovascular and renal diseases including myocardial infarction, heart failure, stroke, and chronic kidney disease. The rising prevalence of hypertension, due in part to changes in diet and food processing, makes it a major global health concern.
Inhigh blood pressure BP was ranked as the leading single risk factor for global burden of disease 2. Evidence from our group and others has demonstrated that hypertension is an inflammatory disease characterized by T cell activation, infiltration of target organs such as the kidney and vasculature, and production of cytokines that lead to salt and water retention, vascular dysfunction, and renal injury 3 — 6.
Most notably, we previously demonstrated that mice deficient in the proinflammatory cytokine ILA exhibit blunted hypertension, attenuated vascular inflammation, and preservation of vascular function in response to angiotensin II—induced Ang II—induced hypertension 7. Recently, we showed that ILA regulates proximal and distal renal sodium transporters and contributes to Ang II—induced renal injury 6.
Of note, numerous epidemiological and experimental studies have demonstrated a link between dietary salt intake and hypertension 9. Interestingly, there is now emerging evidence that salt can directly influence immune cell function.
Frontiers | Macrophages in homeostatic immune function | Physiology
Two recent studies demonstrated that elevated extracellular sodium chloride concentrations of mM, presumably similar to levels found in the interstitium of animals fed a high-salt diet 1011promoted the polarization of naive T cells into Th17 cells through a serum- and glucocorticoid-regulated kinase 1—dependent SGK1-dependent pathway 12 Using a mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis EAEWu et al.
Interestingly, mice with T cell deficiency of SGK1 exhibited a significantly reduced EAE incidence and severity that was not further exacerbated by high-salt feeding. Thus, in addition to regulating salt responsiveness of T cells, SGK1 appears to mediate salt-independent T cell, and particularly Th17 cell, pathogenicity in autoimmune disease.
Given the importance of ILA in hypertension, we therefore hypothesized that T cell SGK1 plays a key role in salt-dependent and -independent hypertension and hypertensive end-organ damage. To test this hypothesis, we generated mice with T cell—specific deletion of SGK1 and induced hypertension using Ang II infusion or uninephrectomy followed by deoxycorticosterone acetate—salt DOCA-salt treatment.
Furthermore, we detected the expression of multiple sodium channels and sodium transporters on T lymphocytes and provide evidence that the sodium-potassium-2 chloride cotransporter 1 NKCC1 is upregulated in Th17 cells and mediates the salt-induced increase in SGK1 and the IL receptor ILR.
T cells that express CD4 at any stage during development should undergo cre recombination and deletion of SGK1. As a secondary control, to confirm that cre recombinase expression in T cells is not responsible for the blunted hypertensive phenotype, we measured BP in tgCD4cre mice at baseline and weekly 2 days per week using carotid radiotelemetry during 28 days of Ang II infusion.
We and others have shown that Ang II increases total leukocyte and T cell infiltration into the perivascular fat and kidneys, and that this is likely an important causal factor for the progression of hypertension and the development of end-organ damage 414 Representative flow cytometry dot plots and gating strategy to detect renal inflammation are shown in Figure 3A.
Following 1 week of Ang II infusion, we did not detect an increase in inflammatory cells in the kidney in either group. Thus, the early phase of Ang II—induced hypertension is associated with an innate immune cell infiltration in the aorta, while the chronic phase of hypertension is associated an increase in T cells in both the aorta and kidney.
T cell SGK1 appears to be necessary for this chronic phase of renal and vascular inflammation. B—D Summary data of absolute numbers of indicated cell types per thoracic aorta. B—D Summary data of absolute numbers of indicated cell types per kidney. Hypertension is characterized by endothelial dysfunction and renal injury 47.
Endothelium-independent relaxation in response to sodium nitroprusside was not affected by Ang II infusion in both groups of mice Figure 4, C and D. Of note, 1 week of Ang II infusion was not sufficient to induce endothelium-dependent impairment in vascular reactivity in either group Supplemental Figure 4.
E Urinary albumin to creatinine ratio in the indicated groups. For these experiments, we used tgCD4cre mice as a secondary control. Taken together, our results show that the absence of renal and vascular inflammation following chronic Ang II infusion in T cell SGK1—deficient mice correlates with protection from Ang II—induced glomerular and vascular injury. Thus, T cell SGK1 appears to play an important role in both salt-dependent and -independent hypertension. Furthermore, these authors demonstrated that SGK1 activation in T cells leads to increased transcription of the ILR through phosphorylation and inhibition of the transcriptional repressor FoxO1.