Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats

Abstract

Immunocompetent cells infiltrate the kidney in several models of experimental hypertension. We have previously shown that reduction of this infiltrate results in prevention of salt-sensitive hypertension induced by short-term angiotensin II infusion and nitric oxide inhibition (Quiroz Y, Pons H, Gordon KI, Rincón J, Chávez M, Parra G, Herrera-Acosta J, Gómez-Garre D, Largo R, Egido J, Johnson RJ, and Rodríguez-Iturbe B. Am J Physiol Renal Physiol 281: F38-F47, 2001; Rodríguez-Iturbe B, Pons H, Quiroz Y, Gordon K, Rincón J, Chávez M, Parra G, Herrera-Acosta J, Gómez-Garre D, Largo R, Egido J, and Johnson RJ. Kidney Int 59: 2222-2232, 2001). We therefore studied whether hypertension could be controlled in genetically hypertensive rats [spontaneously hypertensive rats (SHR)] by the administration of 20 mg x kg(-1) x day(-1) of the immunosuppressive drug mycophenolate mofetil (MMF group; n = 35). Other SHR received vehicle (n = 35), and Wistar-Kyoto rats (n = 20) were used as controls. MMF or vehicle was given in two separate 4-wk periods, separated by a 3-wk interval. Systemic hypertension was reduced to normal levels in both periods of MMF treatment in association with a reduction in lymphocyte, macrophage, and angiotensin II-positive cells infiltrating the kidney. Oxidative stress was also reduced by MMF, as indicated by a reduction in urinary malondialdehyde (MDA), renal MDA content, and superoxide-positive cells, and was highly correlated with blood pressure levels. We conclude that the renal immune infiltrate plays a major role in the hypertension in SHR.

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

“…We did not measure the activity or levels of components of the RAAS in our rats, and it is possible that the system is upregulated in this model of renal disease. For example, it has been reported that expression of AT1R is increased in the inflamed renal parenchyma (41)(42)(43)(44)(45). Therefore, it is reasonable to speculate that higher dosages of candesartan were needed to block completely the increased numbers of AT1R in the diseased SHR kidney.…”

Hypertension as an autoimmune and inflammatory disease

“…12 Furthermore, several experimental studies, in which renal tubulointerstitial inflammation was reduced using various methods, either prevented the development of hypertension altogether or ameliorated hypertension in genetic models of hypertension. 13,14 Putative mechanisms by which increased renal interstitial inflammation leads to the development of hypertension include increased oxidative stress, loss of peritubular capillaries and resultant medullary hypoxia, and an impaired pressure natriuresis mechanism. Details of the mechanisms by which renal interstitial inflammation may cause hypertension have been recently reviewed elsewhere.…”

Hypertension augments cardiac Toll-like receptor 4 expression and activity

“…We hypothesized that hypertension is accompanied by enhanced TLR4 expression and activity. Cardiac TLR4 expression was determined in untreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY;4,8, 16 weeks). Besides, hearts of 8-week-old rats were stimulated with the endogenous TLR4 ligand heparansulfate (HS); the proinflammatory mRNA pattern was assessed (tumor necrosis factor-a (TNF-a), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1).…”