HSP70 and Primary Arterial Hypertension.

Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high interspecies homology. HSP70 has both chaperone and cytokine functions and may induce, depending on the context, tolerogenic anti-inflammatory reactivity or immunogenic and autoimmune reactivity. Intracellular (chaperoning transit of antigens to MHC in antigen-presenting cells) and extracellular HSP70-related effects are associated with hypertension, which is an inflammatory condition recognized as the most important risk factor for cardiovascular disease mortality. Here, we review (a) the relationship between HSP70, inflammation and immune reactivity, (b) clinical evidence relating to stress, HSP70 and anti-HSP70 reactivity with primary hypertension and (c) experimental data showing that salt-sensitive hypertension is associated with delayed hypersensitivity to HSP70. This is a consequence of anti-HSP70 reactivity in the kidneys and may be prevented and corrected by the T-cell-driven inhibition of kidney inflammation triggered by specific epitopes of HSP70. Finally, we discuss our postulate that lifelong stress signals and danger-associated molecular patterns stimulate HSP-70 and individual genetic and epigenetic characteristics determine whether the HSP70 response would drive inflammatory immune reactivity causing hypertension or, alternatively, would drive immunomodulatory responses that protect against hypertension.

Elevated second-trimester maternal serum ß-human chorionic gonadotropin and amniotic fluid alpha-fetoprotein as indicators of adverse obstetric outcomes in fetal Turner syndrome.

AIM: The objective of this study was to determine the ability of biochemical analytes to identify adverse outcomes in pregnancies with Turner syndrome. METHODS: Maternal serum and amniotic fluid (AF) marker concentrations were measured in 73 singleton pregnancies with Turner syndrome (10-22 weeks of gestation). Fetal Turner syndrome was definitively established by cytogenetic analysis. Two subgroups, fetuses with hydrops fetalis versus fetuses with cystic hygroma, were compared. Receiver operating characteristic curves and relative risk were established for a cut-off multiples of the median ≥3.5 for ß-subunit of human chorionic gonadotropin (hCG) or AF alpha-fetoprotein (AFP). RESULTS: Forty-nine (67%) of 73 pregnant women had an abnormal maternal serum. While levels of pregnancy-associated plasma protein-A and free ß-subunit (fß)-hCG were not different to those of the control group, AFP, unconjugated estriol and ß-hCG concentrations were significantly different in the study group (P < 0.05), when compared to those of unaffected pregnancies. Levels of ß-hCG in pregnancies with hydrops fetalis were significantly higher than in those with cystic hygroma (P <0.0001), as were AF-AFP concentrations (P <0.0015). In addition, abnormalities in both maternal serum ß-hCG and AF-AFP predicted fetal death. The relative risk of adverse obstetric outcome was 10.667 (P = 0.0004; 95% confidence interval [CI]: 1.554-73.203) for ß-hCG and 2.19 (P = 0.0256; 95% CI: 1.001 to 4.779), for AF-AFP. CONCLUSION: Maternal serum ß-hCG and AF-AFP levels may preferentially identify those Turner syndrome pregnancies with the highest risk of fetal death.

Autoimmunity in the pathogenesis of hypertension.

Hypertension affects more than one-third of the adult population of the world. However, the cause of high blood pressure is unknown in the vast majority of patients, classified as patients with essential hypertension. Evidence accumulated over the past decade supports the participation of inflammation in the development of experimental hypertension. Investigations have also demonstrated that immune reactivity to overexpressed heat shock protein 70 (HSP70) is involved in the pathogenesis of salt-induced hypertension. This article reviews, first, the role of T cell-induced inflammation in the arteries, kidney and central nervous system in hypertension and the amelioration of hypertension induced by regulatory T cells. Second, experiments showing that autoimmunity directed to HSP70 in the kidney impairs the pressure natriuresis relationship and has a pivotal role in the pathogenesis of salt sensitive hypertension. Finally, we highlight the clinical evidence that supports the participation of autoimmunity in essential hypertension.

Dengue nonstructural protein-1 status is not associated to circulating levels of interleukin-17, C-reactive protein and complement in children with acute dengue.

BACKGROUND: During dengue infection increase in plasma level of various substances have been reported. Some of those molecules are related to the virus biology and others result of the interaction virus-host. Nonstructural protein-1 (NS1) secreted by dengue virus has been reported to have a role in dengue pathogenesis. NS1 is capable of interacting with complement to evade viral clearance. However, there is little information about the presence of serum NS1 and the levels of other molecules related to dengue pathogenesis. OBJECTIVES: The aim of this study was to determine the association of the NS1 status and the circulating levels of interleukin-17 (IL-17), C-reactive protein (CRP), C3 and C4 in acute dengue. STUDY DESIGN: In this study the serum presence of NS1, IL-17, CRP, C3 and C4 was determined in children with acute dengue. IL-17, CRP, anti dengue-IgG content was measured by ELISA, C3 and C4 levels by an immunoturbidimetric assay and NS1 by an immunochromatographic assay. RESULTS: All patients were positive for dengue infection as shown by antibodies anti-dengue and/or virus isolation. Increased levels of IL-17, CRP and C4 no related to the presence of NS1 were found in the patients. Values of C3 remained similar to controls. CONCLUSIONS: These findings suggest that NS1 does not module the production of studied molecules during dengue infection.

Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension.

Hypertension affects one-third of the adult population of the world. The causes of hypertension are incompletely understood, but relative impairment of sodium excretion is central to its pathogenesis. Immune cell infiltration in the kidney is a constant finding in hypertension that in association with local angiotensin and oxidants causes a defect in sodium excretion. However, it is unclear if the T cell influx into the kidney responds to nonspecific chemokine cues or is due to antigen-driven immune attraction. We found that T cells in experimentally induced salt-driven hypertension present a CD4 clonal response to heat shock protein 70 (HSP70) that is overexpressed in the kidney. We used a highly preserved amino acid sequence within the HSP molecule to induce immune tolerance associated with the generation of IL-10 producing regulatory T cells. Immune tolerant rats to HSP70 developed minimal renal inflammation and were protected from the development of salt-sensitive hypertension. Adoptive transfer of T lymphocytes isolated from spleen of tolerized rats also reversed hypertension. HSP70 gene delivery to the renal vein of the kidneys of rats sensitized to HSP70 caused an increment in blood pressure in response to a high-salt diet. The HSP70 peptide used in this work induces a strong proliferative response in peripheral blood lymphocytes of patients with essential hypertension. These studies provide evidence that autoimmunity plays a role in salt-sensitive hypertension and identifies HSP70 expressed in the kidney as one key antigen. These findings raise the possibility of novel approaches to the treatment of this condition.

Respiratory syncytial virus infection increases regulated on activation normal T cell expressed and secreted and monocyte chemotactic protein 1 levels in serum of patients with asthma and in human monocyte cultures.

BACKGROUND: Respiratory syncytial virus (RSV) infection is associated to episodic exacerbations of asthma involving alveolar macrophages and chemokine production. OBJECTIVE: The aim of this study was to determine the circulating levels of monocyte chemotactic protein 1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), and substance P (SP) in patients with and without asthma with acute respiratory RSV infection and the chemokine profile in RSV- infected monocyte cultures from normal individuals and individuals with asthma. METHODS: In this regard, 31 adult patients with acute respiratory infection (15 patients with asthma) were studied. MCP-1, RANTES and SP were measured in serum and in supernatants from monocyte cultures by enzyme-linked immunosorbent assay (ELISA). RESULTS: Increased levels of MCP-1 and RANTES were observed in serum from patients with asthma related to RSV infection. RSV-infected monocyte cultures from healthy individuals showed increased content of those chemokines, and monocyte cultures from patients with asthma showed increased expression of MCP-1. CONCLUSION: These data show that RSV infection induces increased circulating level of chemokines in patients with asthma, and this finding could be mediated in part by the interaction virus-monocyte.

Chronic sildenafil treatment corrects endothelial dysfunction and improves hypertension.

BACKGROUND: Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothelial function and arterial structure. Many of the biological actions of NO are mediated by 3'5'-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Short-term cardiovascular effects of PDE inhibitors have been studied but the changes resulting from their chronic administration in hypertension have not been evaluated. We investigated if retarding the degradation of cGMP by long-term inhibition of PDE-5 would have beneficial consequences in spontaneously hypertensive rats (SHR), a commonly used experimental model of human essential hypertension. METHODS: Subgroups of hypertensive 13-week-old male SHR and normotensive Wistar-Kyoto rats were treated with sildenafil, 2.5 mg/kg/day, or vehicle, by gastric gavage for 6 months. RESULTS: As expected, the untreated SHR had endothelial dysfunction and a steady increment of the blood pressure. In contrast, chronic sildenafil administration reversed endothelial dysfunction, reduced renal oxidative stress and renal macrophage accumulation, and ameliorated the severity of hypertension in SHR. CONCLUSIONS: These results demonstrate beneficial effects of long-term PDE-5 inhibition in SHR and suggest that its use as an adjunct therapy in essential hypertension should be investigated.

Experimental induction of salt-sensitive hypertension is associated with lymphocyte proliferative response to HSP70.

Renal tubulointerstitial inflammation is a constant feature of experimental models of hypertension and likely plays a role in the pathogenesis of salt-sensitive hypertension. We have previously raised the possibility that the immune cell infiltration is driven by a low grade autoimmune reactivity directed to or facilitated by renal heat shock protein over expression. The present studies were done to gain insight on possible cell-mediated immune mechanisms in experimental hypertension by determining the renal expression of HSP70 and the proliferation index of T lymphocytes cultured with HSP70. We studied male Sprague-Dawley rats with inhibition of nitric oxide (NO) synthase (n=6), protein overload (PO) proteinuria (n=7) and short-term angiotensin II (Ang II) infusion (n=5), and their corresponding control groups. Each model was associated with 2 to 4 fold increase (P<0.05-0.001) in renal HSP70 expression. T cells isolated from the spleens demonstrated a significant two- to nine-fold response compared to controls (P<0.05 or lower for each comparison) when cultured with HSP70. These studies suggest that autoimmunity to stress proteins is involved in the sustained low-grade inflammatory infiltration that occurs in the tubulointerstitial areas of the hypertensive kidney.

Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage.

BACKGROUND: Chronic renal disease is associated with oxidative stress and reduced nitric oxide availability which, in turn, promotes hypertension and further progression of renal damage. Most actions of nitric oxide are mediated by cyclic 3',5' guanosine monophosphate (cGMP) which is rapidly degraded by phosphodiesterases (PDE). Therefore, we investigated if inhibition of PDE-5 would retard the progression of chronic renal failure. METHODS: We studied rats with 5/6 nephrectomy treated with sildenafil (2.5 mg/kg(-1)/day(-1)) in two experimental protocols. In the first protocol, we started sildenafil therapy immediately after renal ablation and continued treatment for 8 weeks. Control groups consisted of rats with renal ablation treated with drug-free vehicle and sham-operated rats with and without sildenafil treatment. RESULTS: In these studies, sildenafil treatment prevented hypertension and deterioration of renal function, reduced histologic damage, inflammation and apoptosis, delayed the onset of proteinuria, and preserved renal capillary integrity. In the second protocol we compared sildenafil with losartan (7.5 mg/kg(-1)/day(-1)) and the combination of both drugs in established renal disease, starting these drugs 4 weeks after 5/6 nephrectomy. Delayed sildenafil treatment failed to improve proteinuria and glomerulosclerosis but ameliorated hypertension and azotemia. CONCLUSION: These observations suggest that currently available PDE-5 inhibitors have potential clinical value in the treatment of chronic renal disease.

[Gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and interleukins 2, 4 and 6 (IL-2, IL-4, IL-6) in cervical-uterine cells of intraepithelial neoplasia: a preliminary report]. / Expresión de interferon gamma (IFN-gamma), factor de necrosis tumoral alfa (TNF-alpha) e interleucinas 2, 4 y 6 ( IL-2, IL-4, IL-6) en células de neoplasias intraepiteliales de cuello uterino: reporte preliminar.

The purpose of this work was to determine the expression of type Th1 cytokines: IL-2 and IFNgamma, and Th2: IL-4 and IL-6, as well as TNF-alpha in patients with precancerous lesions of the uterine cervix and their relationship with the human papiloma virus (HPV). 30 patients with precancerous lesions (NIC 1: 70%, NIC 2: 16.7% and NIC 3: 1.3%) and 9 normal controls were studied. A clinical history, gynecological evaluation, cytology and an uterine biopsy were carried out in each patient and control. PCR was used for the diagnosis of HPV. IFN-gamma expression (positive cells/field) was increased in patients with NIC (5.06 +/- 4.7 vs 0 in the control group; p < 0.05). TNFa was a little higher in pathologycal tissues than in the controls (5.23 +/- 3.63 vs 1.55 +/- 2.65; p < 0.05). IL-2 was higher in pathologycal cases than in the controls (8.73 +/- 5.23 vs 0.33 +/- 1, p < 0.05). IL-4 were expressed in both, patients and controls (6.53 +/- 5.23 vs 5.77 +/- 7.32). IL-6 was also higher in patients (4.63 +/- 3.34 vs 0.77 +/- 2.33; p < 0.05). When the HPV status was considered, only IFN-gamma (p < 0.05) and IL-2 (p < 0.05) were significantly higher in HPV positive patients (n = 4) compared to controls. When HPV+ patients were compared with HPV- patients, only IFNgamma was significant (11.5 +/- 5 vs 4.07 +/- 3.8; p < 0.05). In conclusion, Type Th1 immune response prevails in patients with precancerous lesions, whether they are HPV positive or not.

Expresión de interferón gamma (IFN-g), factor de necrosis tumoral alfa (TNF-a) e interleucinas 2, 4 y 6 (IL-2, IL-4, IL-6) en células de neoplasias intraepiteliales de cuello uterino: reporte preliminar / Gamma interferon (IFN-g), tumor necrosis factor alpha (TNF-a) and interleukins 2, 4 and 6 (IL-2, IL-4, IL-6) in cervical-uterine cells of intraepithelial neoplasia: a preliminary report

El presente estudio fue realizado para determinar la expresión de citocinas tipo Th1: IL-2 y IFN-g, y Th2: IL-4 e IL-6, así como del TNF-a en pacientes con lesiones premalignas del cuello uterino (CU) y su relación con la infección por el Virus del Papiloma Humano (VPH). Se estudiaron 30 pacientes con lesiones pre-malignas del CU; NIC 1: 70 por ciento, NCI 2: 16,7 por ciento y NIC 3: 13,3 por ciento) y 9 controles con CU sanos. A cada paciente se le realizó una historia clínica, evaluación ginecológica que incluyó la toma de la citología cervico-vaginal (CCV) y biopsia de CU para estudio histológico e inmunológico. Se empleó la reacción en cadena de polimerasa (PCR) para el estudio del VPH. La expresión del IFN-g se encontró aumentada en pacientes con respecto al grupo control (5,06 ± 4,7 vs 0 media ± DS; p < 0,05). El TNF-a se expresó discretamente elevado en los diferentes tipos de lesiones con respecto al grupo control (5,23 ± 3,63 vs 1,55 ± 2,65; p < 0,05). La IL-2 se encontró más elevada en los casos patológicos que en los controles (8,73 ± 5,23 vs 0,33 ± 1, p < 0,05). La IL-4 se expresó de manera no significativa en tejidos patológicos al compararlo con los controles (6,53 ± 5,23 vs 5,77 ± 7,32). La expresión de la IL-6 fue más elevada en las pacientes que en los controles (4,63 ± 3,34 vs 0,77 ± 2,33; p < 0,05). Al comparar pacientes VPH positivos con los controles, solo el IFN-g (p < 0,05) y la IL-2 (p < 0,05) fueron significantes. Sólo el IFN-g fue significativo al comparar pacientes con o sin VPH (11,5 ± 5 vs 4,07 ± 3,8 p < 0,007). La respuesta inmunitaria tipo Th1 predomina en las lesiones premalignas, esté presente o no el VPH

Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition.

BACKGROUND: Angiotensin II (Ang II) infusion and nitric oxide synthesis (NOS) inhibition with Nomega-nitro-l-arginine-methyl-ester (l-NAME) are experimental models of hypertension associated with renal inflammation and oxidative stress. To gain insight into the nature of the tubulointerstitial injury induced in these models, we studied lectin-binding specificities, vimentin expression, and heat shock protein (HSP) 60 and 70 in these experimental models. METHODS: Sprague-Dawley rats received Ang II infusion (435 ng/kg/min) for 2 weeks by subcutaneous minipumps (Ang II group, N = 5) or l-NAME in the drinking water (70 mg/100 mL) for 3 weeks (l-NAME group N = 7). The control group consisted of 10 rats. Systolic blood pressure (tail-cuff plethysmography), serum creatinine, and proteinuria were determined weekly. At the end of the treatment period, rats were sacrificed and kidneys studied. Binding specificities of fluorescein-labeled lectins were examined in frozen sections, and cellular infiltrates were identified by immunohistology and expression of vimentin and HSP 60 and 70 with immunohistochemistry and computer image analysis. RESULTS: Tubulointerstitial accumulation of macrophages, lymphocytes, and Ang II-positive cells were present in the Ang II group and l-NAME group. Vimentin, HSP 60, and HSP 70 were increased 8 to 20 times in the cortex of the rats of the Ang II group and the l-NAME groups. Neoexpression of vimentin and HSPs was found primarily in proximal tubular cells. CONCLUSION: Ang II infusion and NOS inhibition induce tubular injury with epithelial cell transdifferentiation and expression of stress proteins. The role of these changes in the accumulation and activation of the interstitial inflammatory infiltrate merits further investigation.

Melatonin increases interleukin-1beta and decreases tumor necrosis factor alpha in the brain of mice infected with the Venezuelan equine encephalomyelitis virus.

The effect of melatonin (MLT) on the brain levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in Venezuelan equine encephalomyelitis (VEE) virus infection was determined. Brain homogenates from mice inoculated with 10 LD50 of VEE virus, untreated or treated with 500 microg MLT/kg body weight were assayed by ELISA to measure the levels of TNF-alpha and IL-1beta. MLT was injected daily starting 3 days before and continuing to 7 days after virus inoculation. Infected mice treated with MLT showed decreased levels of TNF-alpha when compared to the untreated infected mice on days 1, 3, 4, and 5 postinoculation (P < 0.001). In contrast, IL-1beta levels increased from days 1 to 5 in the infected mice treated with MLT when compared with the untreated infected animals (P < 0.01). The results suggest that the protective effect of MLT on the VEE virus infection could be due, among other factors, to a decrease in TNF-alpha synthesis along with an increase in the production of IL-1beta.

[Effect of melatonin on lymphocyte proliferation and production of interleukin-2 (IL-2) and interleukin-1 beta (IL-1 beta) in mice splenocytes]. / Efecto de la melatonina en la proliferación linfocitaria y la producción de interleucina 2 (IL-2) e interleucina 1 beta (IL-1 beta) en esplenocitos de ratones.

The influence of Melatonin (MLT) on the modulation of the immune system has been described. In previous studies an increment of cell proliferation and an increase or a decrease of cytokines have been reported. Other workers have found inhibitory effects or no effect in the immune functions. Because of this controversy, and for the purpose of studying the mechanism by which MLT performs its functions, we evaluated its effect on murine splenocytes's proliferation after a mitogenic stimulation, and quantified the levels of IL-2 and IL-1 beta in the absence or presence of Phitohemaglutinin (PHA) in supernatants of mice splenocytes cell culture treated or not with MLT. The lymphoproliferative response was assessed using tritiated thimidine in the splenocytes of mice treated with 500 micrograms of MLT/Kg b.w. and in cell cultures containing 5, 50 and 100 micrograms MLT/mL. The production of IL-2 and IL-1 beta was detected by the ELISA test. An increase in the proliferation (p < 0.01) of spleen cells treated with 50 and 100 micrograms MLT/mL an optimal dose of PHA, was detected. The in vivo or in vitro treatment with MLT increased the levels of IL-2 and IL-1 beta in the absence or the presence of PHA, maintaining the increase in the concentration of IL-1 beta up to the to ninth day of treatment. These results suggest that MLT acts directly on cell proliferation probably by binding to high affinity receptors located on spleen cells, that stimulates the production of IL-2 and IL-1 beta giving rise to an increment of cell immunity.

Efecto de la melatonina en la profileración linfocitaria y la producción de interleucina 2 (IL-2) e enterleucina 1 beta (IL-1ß) en esplenocitos de ratones / Effect of melatonin on lymphocyte proliferation and production of interleukin-2 (IL-2) and interleukin-1-beta (IL-1ß) is splenocytes of mice

La melatonina (MLT) influye en la modulación del sistema inmunitario. Previos estudios describen incremento de la proliferación celular con aumento o disminución de citocinas; otros autores reportan efectos inhibitorios o ningún efecto en las funciones inmunitarias. debido a esta controversia, y con el objeto de estudiar el mecanismo mediante el cual la MLT ejerce sus acciones, se planteó examinar su efecto en la proliferación de esplenocitos múridos ante un estímulo mitogénico y cuantificar los niveles de IL-2 e IL-1ß en ausencia o presencia de la Fitohemaglutinina (PHA) en sobrenadantes de cultivo de células esplénicas de ratones tratados o no con MLT. La respuesta linfoproliferativa se evaluó utilizando la incorporación de timidina marcada con tritio, en esplenocitos de ratones tratados con 500 µg de MLT/Kg de peso e in vitro con 5,50 y 100 µg/mL de MLT. La detección de IL-2 e IL-1ß se realizó con la técnica de ELISA. Se observó una elevación (p<0,01) de la proliferación, a dosis óptima de PHA, de los esplenocitos tratados in vitro con 50 y 100 µg/mL de MLT, con respecto al grupo control. El tratamiento in vivo e in vitro con MLT incremetó los niveles de IL-2 e IL-1ß en ausencia o presencia de PHA, manteniendo elevada la concentración de IL-1ß hasta el noveno día de tratamiento. Estos resultados sugieren que la MLT actúa en forma directa en la proliferación linfocitaria uniéndose, posiblemente, a los receptores de alta afinidad para la hormona localizados en los esplenocitos, que estimula la producción de IL-2 e IL-ß originando un incremento de la inmunidad celular

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

Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 +/- 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg. kg(-1). day(-1)) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 +/- 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.

Melatonin induces changes to serum cytokines in mice infected with the Venezuelan equine encephalomyelitis virus.

We determined the influence of melatonin (MLT) on the induction of interleukin (IL)-2, IL-1 beta, IL-4, tumour necrosis factor-alpha (TNF-alpha) and gamma interferon (IFN-gamma) on mice infected with the Venezuelan equine encephalomyelitis (VEE) virus. Levels of IFN-gamma in the MLT-treated group were significantly increased (P < 0.001) when compared with the control non-infected group from day 1 to 6 post-infection (p.i.), while in infected mice treated with 500 micrograms MLT/kg of bodyweight enhanced levels of IFN-gamma were evident from 4 to 6 days p.i. No differences were detected in the levels of IL-2 between the controls, the infected mice treated with MLT and the infected untreated group, from day 2 p.i. No changes in serum levels of IL-4 were detected. In infected mice treated with MLT, blood levels of IL-1 beta were elevated almost 10-fold from day 1 to day 6 p.i. when compared to the control, the infected and the non-infected MLT-treated mice (P < 0.001). A highly significant rise (P < 0.001) of TNF-alpha was found in infected mice treated with MLT, from day 1 to 6 p.i. when compared to the other groups. A significant rise (P < 0.001) was also evident in the infected non-MLT-treated group and a less pronounced rise in the non-infected mice treated with MLT when compared to controls. The blockade of IFN-gamma and TNF-alpha did not inhibit the protective effect of MLT but when IL-1 beta was neutralized, 100% of the infected mice died suggesting that IL-1 beta induced by MLT treatment is a target cytokine to generate an immune response against the viral infection.

The role of immune cells infiltrating the kidney in the pathogenesis of salt-sensitive hypertension.

This work summarizes recent evidence that suggests that renal infiltration with immune cells plays a role in the pathogenesis of salt-sensitive hypertension. The presence of immunocompetent cells is a conspicuous finding in conditions associated with hypertension induced or maintained by a high salt intake. Studies in models of salt-sensitive hypertension following angiotensin II infusion and nitric oxide synthesis inhibition indicate that a reduction in the tubulointerstitial infiltration of lymphocytes and macrophages during the induction period results in protection from the subsequent development of salt-sensitive hypertension. Reduction of the renal immune infiltrate in spontaneously hypertensive rats results in near normalization of the blood pressure. The reduction in the immune infiltrate is associated with a reduction in the number of cells expressing angiotensin II (some of which are immune cells) and a reduction in renal oxidative stress. Since increased intrarenal angiotensin activity tends to reduce filtered sodium and increase sodium reabsorption, and the tubulointerstitial damage resulting from oxidative stress can induce a shift to the right in the pressure-natriuresis relationship, these findings suggest potential mechanisms by which the immune infiltrate could induce or worsen salt-driven hypertension.

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

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.

Renal cortical vasoconstriction contributes to development of salt-sensitive hypertension after angiotensin II exposure.

Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 +/- 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngII+MMF showed similar responses to AngII; however, they developed lower proteinuria (P < 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 +/- 8.2 mmHg at week 1 and 163 +/- 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and single-nephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngII+MMF group, SBP remained unchanged throughout the HSD period (146 +/- 2.3 mmHg at week 1 and 148 +/- 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.