Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells

Álvarez, V; Quiroz, Yasmir; Nava, Manuel; Pons, Héctor; Rodríguez‐Iturbe, Bernardo

doi:10.1152/ajprenal.00199.2002

Cited by 99 publications

(143 citation statements)

References 47 publications

(81 reference statements)

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“…Indeed, we have noted a remarkable relationship between the presence of T cells and macrophages in the interstitium with salt-sensitive blood pressure in numerous models. [42][43][44] More importantly, we also found that the reduction of the renal inflammatory response by mycophenolate mofetil could prevent the salt-dependent hypertension that occurs following subcutaneous angiotensin infusion, 42 following the temporary inhibition of nitric oxide synthase 43 and the hypertension that occurs with protein overload nephropathy. 44 Subsequently, a large number of studies from several laboratories, including our own, found that treatments directed to suppress renal inflammation are associated with prevention or amelioration of hypertension.…”

Section: Renal Microvascular Disease and Interstitial Inflammation Armentioning

confidence: 59%

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

Rodríguez‐Iturbe¹,

Johnson

2010

Hypertens Res

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Primary (essential) hypertension has been shown to be mediated by a relative impairment in sodium excretion by the kidney, but the mechanisms responsible for this defect are still being clarified. Increasing evidence suggests a role for subtle acquired renal injury in mediating this process. Microvascular injury is present in the majority of subjects with hypertension. The development of arteriolosclerosis, primarily of the afferent arteriole, may interfere with glomerular autoregulation, whereas the loss of peritubular capillaries may facilitate local ischemia. These changes favor the localization of T cells and macrophages into the interstitium, which, coupled with local oxidative stress and angiotensin II generation, may contribute to the impaired pressure natriuresis observed with salt-sensitive hypertension. Consistent with this hypothesis, therapies that are aimed at blocking the immune response, including thymectomy, genetic alterations in mice resulting in impaired immune responses, or the use of immunosuppressive agents, can protect against the development of hypertension in experimental models. Preliminary data in humans also suggest that the inhibition of the renal inflammatory response may reduce blood pressure. The present investigations are directed to gain insight in the role of the intrarenal T-cell reactivity and autoimmunity in driving the tubulointerstitial inflammation and its participation in the pathogenesis of salt-sensitive hypertension.

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Section: Renal Microvascular Disease and Interstitial Inflammation Armentioning

confidence: 59%

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

Rodríguez‐Iturbe¹,

Johnson

2010

Hypertens Res

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“…Proteinuria was determined in 24-h urines collected at baseline, at 8 wk, and at 12 wk before death. Systolic blood pressure was determined by tail cuff plethysmography (IITC Life Scientific Instruments, Woodland Hills, CA) at baseline and at the end of the experiment as described in previous communications (2,26,33,34). All rats had been preconditioned to the procedure, and at the time when the blood pressure was determined they were allowed to rest in the restrainer for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in rats with renal mass reduction

Quiroz

Ferrebuz²,

Romero³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…10 Several recent studies have provided convincing evidence that the renal proinflammmatory response has an important role in mediating salt-sensitive hypertension. 31,32 In a previous study, quantitative trait locus analysis identified the P2X 7 gene as a candidate gene for hypertension, by using F2 rats derived from DS and LEW rats. 13 In the present study, expression levels of P2X 7 mRNA and protein in the kidneys of DS were much higher than those in the kidneys of LEW with normal diets.…”

Section: P2x 7 Expression Is Higher In the Kidneys Of Ds Ratsmentioning

confidence: 99%

P2X7 receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats

Naito

Hirokawa

et al. 2011

Hypertens Res

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The P2X 7 receptor is a ligand-gated ion channel activated by extracellular ATP, and a common genetic variation in the P2X 7 gene significantly affects blood pressure. P2X 7 receptor expression is associated with renal injury and some inflammatory diseases. Brilliant blue G (BBG) is a selective rat P2X 7 receptor antagonist. In this study, to test whether BBG has protective effects on saltsensitive hypertension and renal injury, Dahl salt-sensitive (DS) rats fed an 8% NaCl diet were i.p. injected with BBG (50 mg kg À1 per day) for 4 weeks. We also tested another P2X 7 receptor antagonist, namely A-438079 (100 mg kg À1 per day), for 7 days. We found that P2X 7 antagonism markedly attenuated salt-sensitive hypertension, urinary protein or albumin excretion, renal interstitial fibrosis and macrophage and T-cell infiltration in the DS rats, and significantly improved creatinine clearance. In an in vitro experiment using macrophages, we showed that lipopolysaccharide (LPS)-primed macrophages from the DS rats released more interleukin-1 beta in response to BzATP, a P2X 7 receptor agonist, than the macrophages from Lewis rats, possibly due to higher P2X 7 expression in the DS rats. In conclusion, in vivo blockade of P2X 7 receptors attenuated salt-sensitive hypertension and renal injury in the DS rats. Thus, P2X 7 appears to be responsible for a vicious cycle of salt-sensitive hypertension and renal injury in the DS rats, through higher expression in the immune cells. Furthermore, P2X 7 antagonists can prevent the development of salt-sensitive hypertension and renal injury, thus confirming that the P2X 7 receptor is an important therapeutic target. INTRODUCTIONThe P2X 7 receptor is an adenosine-5¢-triphosphate (ATP)-gated cation channel that is expressed mainly in certain immune cells, including macrophages and lymphocytes. 1,2 Stimulation of P2X 7 is proinflammatory, resulting in the release of inflammatory cytokines, such as interleukin (IL)-1 beta (b) and IL-18 from macrophages 2-5 and IL-2 from T cells, 5-7 as well as changes in the plasma membrane lipid distribution and cell death by necrosis or apoptosis. 2,3 P2X 7 has been reported to be involved in various nephropathy models, such as glomerular injury caused by diabetes and hypertension, 8 unilateral ureteral obstruction 9 and glomerulonephritis. 10 Dahl salt-sensitive (DS) rats fed on a high-sodium diet characteristically develop attenuated pressure natriuresis, hypertension and progressive renal injury, and this model has been widely used to study salt-sensitive hypertension. 11,12 In a previous study, we performed a genome-wide quantitative trait locus mapping analysis for blood pressure by using F2 rats derived from DS and Lewis (LEW) rats, and we identified a region on chromosome 12 near the D12Arb6 marker that influenced blood pressure. 13 The P2X 7 gene is also near the D12Arb6 marker. A common genetic variation in the region of the P2X 7 gene significantly affects blood pressure in a Caucasian population. 14 Although the pathophysiology of hypertension...

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Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells

Cited by 99 publications

References 47 publications

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in rats with renal mass reduction

P2X7 receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats

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