Salt-sensitive hypertension--update on novel findings.
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Humans↗
Biomedical subjects
Bernardo Rodriguez-Iturbe
Publications and source records attributed to Bernardo Rodriguez-Iturbe.
Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence.
Mitochondria are the major source of superoxide (O(2)(-)) in the aerobic organisms. O(2)(-) produced by the mitochondria is converted to hydrogen peroxide by mitochondrial superoxide dismutase (SOD2). Mice with complete SOD2 deficiency (SOD2(-/-)) exhibit dilated cardiomyopathy and fatty liver leading to neonatal mortality, whereas mice with partial SOD2 deficiency (SOD2(+/-)) show evidence of O(2)(-)-induced mitochondrial damage resembling cell senescence. Since earlier studies have provided compelling evidence for the role of oxidative stress and tubulointerstitial inflammation in the pathogenesis of hypertension, we tested the hypothesis that partial SOD2 deficiency may result in hypertension. Wild-type (SOD2(+/+)) and partial SOD2-deficient (SOD2(+/-)) mice had similar blood pressures at 6-7 mo of age, but at 2 yr SOD2(+/-) mice had higher blood pressure. Oxidative stress, renal interstitial T-cell and macrophage infiltration, tubular damage, and glomerular sclerosis were all significantly increased in 2-yr-old SOD2(+/-) mice. High-salt diet induced hypertension in 6-mo-old SOD2-deficient mice but not in wild-type mice. In conclusion, partial SOD2 deficiency results in oxidative stress and renal interstitial inflammation, changes compatible with accelerated renal senescence and salt-sensitive hypertension. These findings are consistent with the pattern described in numerous other models of salt-sensitive hypertension and resemble that commonly seen in elderly humans.
Animals↗
Nephron number, uric acid, and renal microvascular disease in the pathogenesis of essential hypertension.
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Adolescent↗
Prevention strategies for chronic kidney disease in Latin America: a strategy for the next decade--a report on the Villarica Conference.
Representatives from 19 Latin American countries gathered to report and deliberate on both the present and future implications of the growing epidemic of chronic kidney disease-as well as cardiovascular disease, diabetes, and hypertension-and to define the role that national health systems need to adopt in order to cope with them. Country-by-country reports provided an excellent overview of the current state of health care in general and chronic diseases in particular. The meeting concluded with a consensus statement on the most urgent needs for the next decade.
Awareness↗
Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis.
Evidence that was obtained in several experimental models and in strains of hypertensive rats indicates that infiltration of inflammatory cells and oxidative stress in the kidney play a role in the induction and maintenance of hypertension. Similar evidence is lacking in human hypertension, at least in part, because immunosuppressive treatment is unjustified in patients with hypertension. For addressing this issue, patients who were prescribed by their private physicians mycophenolate mofetil (MMF) for the treatment of psoriasis or rheumatoid arthritis and had, in addition, grade I essential hypertension and normal renal function were studied. Eight patients were studied before MMF was started, during MMF treatment, and 1 mo after MMF treatment had been discontinued. Other treatments and diet were unchanged in the three phases of the study. MMF therapy was associated with a significant reduction in systolic, diastolic, and mean BP. Urinary excretion of TNF-alpha was reduced progressively by MMF treatment and increased after MMF was discontinued. Reduction of urinary malondialdehyde, TNF-alpha, and RANTES excretion during MMF administration did not reach statistical significance but had a direct positive correlation with the BP levels. These data are consistent with the hypothesis that renal immune cell infiltration and oxidative stress play a role in human hypertension.
Aged↗
Hypertension and cardiovascular risk in chronic kidney disease patients.
This supplement of the Journal of American Society of Nephrology contains some of the proceedings of the Fifth International Conference on Hypertension and the Kidney. The Conference, held in Madrid, Spain, in February 2006, was organized by the Department of Nephrology of the Hospital General, Universitario Gregorio Marañón, under the sponsorship of the Universidad Complutense de Madrid, Spanish Society of Nephrology, Spanish Society of Hypertension, and European Renal Association-European Dialysis and Transplant Association.
Cardiovascular Diseases↗
Role of inflammatory cells in the kidney in the induction and maintenance of hypertension.
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Animals↗
IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease.
IL-10 is a pluripotent cytokine that plays a pivotal role in the regulation of immune and inflammatory responses. Whereas short-term administration of IL-10 has shown benefit in acute glomerulonephritis, no studies have addressed the potential benefits of IL-10 in chronic renal disease. Chronically elevated blood levels of IL-10 in rats were achieved by administration of a recombinant adeno-associated virus serotype 1 IL-10 (rAAV1-IL-10) vector. Control rats were given a similar dose of rAAV1-GFP. Four weeks after injection, IL-10 levels in serum were measured by ELISA, and chronic renal disease was induced by a 5/6 nephrectomy (n = 6 in each group). Eight weeks later, rats were killed and renal tissue was obtained for RNA, protein, and immunohistochemical analysis. Serum levels of IL-10 were 12-fold greater in the rAAV1-IL-10 group by 4 wk after rAAV1-IL-10 administration (345 +/- 169 versus 28 +/- 15 pg/ml; P = 0.001), and levels were maintained throughout the experiment. rAAV1-IL-10 treatment resulted in less proteinuria (P < 0.05), lower serum creatinine (P < 0.05), and higher creatinine clearances (P < 0.01) compared with rAAV1-GFP-treated rats. Renal interstitial infiltration was significantly attenuated by rAAV1-IL-10 administration as assessed by numbers of CD4+, CD8+, monocyte-macrophages (ED-1+) and dendritic (OX-62+) cells (P < 0.05), and this correlated with reductions in the renal expression of monocyte (renal monocyte chemoattractant protein-1 mRNA and protein) and T cell (RANTES mRNA) chemokines. rAAV1-IL-10 administration decreased mRNA levels of IFN-gamma and IL-2 in the kidney. The reduction in inflammatory cells was associated with a significant reduction in glomerulosclerosis and interstitial fibrosis. It is concluded that IL-10 blocks inflammation and improves renal function in this model of chronic renal disease. The feasibility of long-term overexpression of a gene using the AAV serotype 1 vector system in a model of renal disease is also demonstrated.
Animals↗
Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT1A and AT1B double-knockout mice.
AT(1) double receptor (AT(1A) and AT(1B)) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT(1) double-knockout mice. We examined the renal expression of various mediator systems in control (n = 6) vs. double-knockout mice (n = 6) at 3-5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT(1) double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4(+) and CD11b(+) cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls (P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor (P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT(1) double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT(2) receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.
Animals↗
Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link?
Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.
Disease Progression↗
Upregulation of angiotensin II type 1 receptor, inflammatory mediators, and enzymes of arachidonate metabolism in obese Zucker rat kidney: reversal by angiotensin II type 1 receptor blockade.
BACKGROUND: Severe obesity can result in proteinuria and progressive glomerulosclerosis in humans and experimental animals. The associated renal disease is ameliorated by weight reduction and/or blockade of the renin-angiotensin system. Various growth factors, cytokines, and lipid mediators are implicated in the pathogenesis of renal disease. To explore the possible involvement of these mediators in obesity-induced renal disease, we examined the expression of key enzymes of arachidonate metabolism and inflammatory genes in untreated and losartan-treated obese Zucker rats, a model of obesity, insulin resistance, and renal injury. METHODS AND RESULTS: Seven-week-old male obese Zucker rats were randomized to losartan-treated (100 mg/L drinking H2O) and untreated groups, with lean Zucker rats as controls. After 4 months, RNA and protein were obtained from renal cortical tissue for relative reverse transcription-polymerase chain reaction, Western blots, and immunohistochemistry. Compared with the lean controls, obese Zucker rats showed significant glomerular matrix expansion and increased mRNA expression of the extracellular matrix protein fibronectin, inflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, and 2 major enzymes of arachidonate metabolism, namely, 12/15-lipoxygenase and cyclooxygenase-2. This was associated with significant increases in p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase activities and marked upregulation of angiotensin II type 1 receptor (AT1R) mRNA and protein expression. These abnormalities and the associated glomerulopathy and proteinuria were prevented by administration of the AT1R blocker losartan. CONCLUSIONS: These findings indicate that obesity-induced glomerulopathy is associated with upregulation of key inflammatory mediators. These events are associated with and perhaps in part due to upregulation of AT1R, as evidenced by their reversal with AT1R blocker treatment.
Angiotensin II Type 1 Receptor Blockers↗
Subtle renal injury is likely a common mechanism for salt-sensitive essential hypertension.
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Animals↗
A unifying pathway for essential hypertension.
We present the hypothesis that most cases of essential hypertension occur via two phases. The first phase is initiated by episodes of renal vasoconstriction induced by a hyperactive sympathetic nervous system, activation of the renin-angiotensin system, or hyperuricemia resulting from diet or genetics. During this phase the hypertension is salt resistant and renin dependent, and the kidney normal. Over time, preglomerular vascular disease develops (arteriolosclerosis), associated with tubulointerstitial inflammation; this shifts the hypertension to a salt-sensitive, volume-dependent, and renal-dependent pathway. This pathway unites many of the previous hypotheses on the etiology of hypertension, and offers insights into ways to prevent, ameliorate, or cure the underlying process.
Animals↗
Hypertension induced by aortic coarctation above the renal arteries is associated with immune cell infiltration of the kidneys.
BACKGROUND: Renal tubulointerstitial infiltration of activated T cells and macrophages is invariably present and plays a role in elevation of arterial pressure in nearly all animal models of hypertension (HTN). The role, if any, of elevated renal arterial pressure in the pathogenesis of this inflammatory process is uncertain. Also unclear is whether the cellular infiltration is caused by the local activation of immune cells in the kidney or a consequence of leukocyte activation in the systemic circulation. METHODS: We studied activation of peripheral blood leukocytes and cellular infiltration in the kidneys of Sprague-Dawley rats with abdominal aorta coarctation (banding) above renal arteries, which causes severe HTN proximal but not distal to coarctation. RESULTS: Compared with the sham operated controls, the aorta-banded group exhibited tubulointerstitial accumulation of activated T cells, macrophages, angiotensin-II positive cells, leukocyte function-associated antigen-1 integrin expressing cells, increased nitrotyrosine abundance (a measure of oxidative stress), and increased macrophage chemoattractant protein-1 in the kidneys which are not exposed to HTN in this model. These findings were associated with the activation of the circulating leukocytes in the aorta-banded animals. CONCLUSIONS: Increased baromechanical stress is not a requisite for accumulation of T cells and macrophages in the kidney in the coarctation-induced HTN and possibly in other hypertensive disorders. On the contrary, renal hypoperfusion and the consequent activation of renin-angiotensin system may mediate this process by promoting local induction of chemoattractant and inflammatory cytokines. The observed tubulointerstitial inflammation in this model is associated with leukocyte activation in the systemic circulation.
Angiotensin II↗
Prevention of chronic kidney and vascular disease: toward global health equity--the Bellagio 2004 Declaration.
Chronic kidney disease (CKD) not only reflects target organ injury in systemic vascular disease in the general population and in association with diabetes, hypertension, and smoking, but it is recognized as one of the major risk factors in the pathogenesis and outcome of cardiovascular disease. Recent surveys have revealed that the prevalence of CKD, particularly the hidden mild form (mildly elevated levels of serum creatinine or urinary albumin excretion), is surprisingly high in the general population. In recent years, the global epidemic of type 2 diabetes has led to an alarming increase in the number of patients with CKD. Most patients with CKD (over 50 million individuals worldwide) succumb to cardiovascular events, while each year over 1 million develop end-stage renal failure, which requires costly treatment and in many countries of the world, unaffordable renal replacement therapy by chronic dialysis or renal transplantation. Alarmed by the immense challenge to human morbidity and the economic burden of CKD and ensuing systemic cardiovascular disease, the International Society of Nephrology convened a multidisciplinary group of expert physicians and public health leaders from around the world to develop strategies to delay and avert this bleak future by effective prevention of CKD based on awareness, early detection, and effective treatment.
Cardiovascular Diseases↗
Demographic and epidemiologic transition in the developing world: role of albuminuria in the early diagnosis and prevention of renal and cardiovascular disease.
The developing world is facing a real pandemic of renal and cardiovascular disease. With the decrease of infectious disease morbidity and mortality, and the exposure to more westernized life style, signs of increasing renal and cardiovascular disease is particularly shown in the tremendous rise in type 2 diabetes and its sequelae. A group of doctors and scientists from all over the world have convened in Bellagio to halt this dramatic disease change and burden to the developing countries. They came to the conclusion that screening and treatment should clearly focus on cost-beneficial strategies, among which blood pressure and urinary albumin measurement, as well as effective and affordable treatment strategies to lower blood pressure and albuminuria, are essential.
Albuminuria↗
Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?
Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.
Animals↗
Hypothesis: dysregulation of immunologic balance resulting from hygiene and socioeconomic factors may influence the epidemiology and cause of glomerulonephritis worldwide.
Glomerular diseases show diverse epidemiological characteristics throughout the world, which has been suggested to be caused by differences in genetics of the underlying populations or environmental exposure to the putative antigens or agents that either trigger or induce the disease. Recently, an alteration in immune balance of the T helper 1 (T(H)1) and T helper 2 (T(H)2) subsets has been implicated as a mechanism to explain the relative increase in allergic diseases in industrialized nations. According to the Hygiene Hypothesis, overcrowding and poor hygiene early in life may protect from atopic diseases because exposure to microbes predisposes in favor of a T(H)1-dominant response. Conversely, dominance of the T(H)2 subset would be responsible for the increasing incidence of allergies. We present the hypothesis that this imbalance may help explain the predilection for membranoproliferative glomerulonephritis (GN) and mesangial proliferative GN to be associated with developing and/or poor nations, whereas immunoglobulin A nephropathy and minimal change disease are observed more commonly in industrialized nations. The implication of the Hygiene Hypothesis is that clinical expression of immune-mediated renal disease would depend on the prevailing T(H)1/T(H)2 balance, rather than the etiologic agent, and it may help explain the epidemiological pattern of glomerular diseases worldwide.
Crowding↗