Angiotensin II, interstitial inflammation, and the pathogenesis of salt-sensitive hypertension

Abstract

Transient administration of ANG II causes persistent salt-sensitive hypertension associated with arteriolopathy, interstitial inflammation, and cortical vasoconstriction; blocking the vascular and inflammatory changes with mycophenolate mofetil (MMF) prevents vasoconstriction. While infiltrating leukocytes during the salt-sensitive hypertension phase express ANG II, the functional role of ANG II during this phase is not known. We examined the acute effect of candesartan on renal hemodynamics during the established salt-sensitive hypertensive phase and related these findings to direct measurement of intrarenal ANG II and inflammatory cells in rats previously exposed to ANG II with or without MMF treatment. Sham controls were also examined. The administration of ANG II, followed by exposure to high-salt diet, resulted in hypertension, cortical vasoconstriction, an increase in interstitial inflammatory cells (44.8 +/- 1.3 lymphocytes/mm2, and 30.8 +/- 1.2 macrophages/mm2 ANG II vs. 19.6 +/- 2 lymphocytes/mm2, and 22 +/- 0.7 macrophages/mm2 Sham), and increase in renal ANG II levels (1,358 +/- 74.6 pg/ml ANG II vs. 194 +/- 9.28 pg/ml Sham). Treatment with MMF during the administration of exogenous ANG II resulted in reduction in renal interstitial inflammation (19.7 +/- 0.9 lymphocytes/mm2 and 15.9 +/- 0.8 machophages/mm2), ANG II levels (436.9 +/- 52.29 pg/ml), cortical vasoconstriction, and stable blood pressure levels during the subsequent challenge with a high-salt diet. Acute administration of candesartan similarly reduced renal vasoconstriction and blood pressure. We conclude that the cortical vasoconstriction occurring with salt-sensitive hypertension following exposure to ANG II is mediated by intrarenal ANG II, related, at least in part, to the interstitial inflammation.

Immunosuppression preserves renal autoregulatory function and microvascular P2X1 receptor reactivity in ANG II-hypertensive rats

“…Notably, suppression of lymphocyte activation and proliferation with MMF significantly reduced lymphocyte infiltration in cortical tissue and preserved both pressure-and P2X 1 receptor-mediated vasoconstriction in ANG II-hypertensive rats. The progression and magnitude of hypertension induced by ANG II infusion, however, were not significantly altered by MMF, consistent with observations in the 5/6 nephrectomy, L-NAMEand ANG II-induced hypertensive models in rats or mice (5,7,22,28) but different from what has been reported for the DOCA-salt and Dahl salt-sensitive hypertensive models (3,6). Overall, the current results suggest that activated lymphocytes are associated with renal microvascular dysfunction in ANG II-hypertensive rats.…”

Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney

“…In hypertension induced by angiotensin II, Mattson et al (26) and Wang et al (52) found a progressive increment in GFR with increasing RAP pressure, similar to what we observed in the SSHTN group. In addition, inflammatory cytokines, such as transforming growth factor ␤, impair the autoregulation of glomerular hemodynamics via the generation of reactive oxygen species (13,47) and may cause afferent arteriolar remodeling (7,46). Taken together, these findings suggest that the loss of GFR autoregulation in the SSHTN group may be related to renal angiotensin II overactivity and renal inflammation.…”

“…This may be due to reduced oxygen delivery to regions of the kidney that function normally under relative hypoxia, causing a further reduction in oxygen partial pressure with the generation of oxidative stress and impaired pressure natriuresis (16). In addition, the infiltration of immune-competent cells in the renal interstitial space is associated with inflammation-induced generation of reactive oxygen species and increased local angiotensin II activity (7,41,42,51) that suppress natriuresis.The present investigations were directed to test the assumption that a consequence of tubulointerstitial inflammation is the blunting of the pressure-natriuresis response. In these studies, we selected an experimental model of SSHTN that follows recovery from nitric oxide synthase inhibition with N -nitro-L-arginine methyl ester (L-NAME) (34).…”

“…This may be due to reduced oxygen delivery to regions of the kidney that function normally under relative hypoxia, causing a further reduction in oxygen partial pressure with the generation of oxidative stress and impaired pressure natriuresis (16). In addition, the infiltration of immune-competent cells in the renal interstitial space is associated with inflammation-induced generation of reactive oxygen species and increased local angiotensin II activity (7,41,42,51) that suppress natriuresis.…”

Dietary salt intake is related to inflammation and albuminuria in primary hypertensive patients

“…8,9 Inflammatory mechanisms have been proposed to have a role in this nephrotoxic effect of salt excess. [9][10][11][12][13] The role of inflammation in the initiation and progression of cardiovascular diseases is increasingly recognized. 14,15 Studies in hypertensive individuals have shown increased plasma and vascular tissue levels of C-reactive protein (CRP) and several inflammatory cytokines, suggesting a potential association between vascular inflammation and hypertension.…”