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Renal Tumor Necrosis Factor α Contributes to Hypertension in Dahl Salt-Sensitive Rats.

ABSTRACT: Tumor necrosis factor α (TNFα) is a major proinflammatory cytokine and its level is elevated in hypertensive states. Inflammation occurs in the kidneys during the development of hypertension. We hypothesized that TNFα specifically in the kidney contributes to the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats, a widely used model of human salt-sensitive hypertension and renal injury. SS rats were chronically instrumented for renal interstitial infusion and blood pressure measurement in conscious, freely moving state. Gene expression was measured using real-time PCR and renal injury assessed with histological analysis. The abundance of TNFα in the renal medulla of SS rats, but not the salt-insensitive congenic SS.13(BN26) rats, was significantly increased when rats had been fed a high-salt diet for 7 days (n = 6 or 9, p < 0.01). The abundance of TNFα receptors in the renal medulla was significantly higher in SS rats than SS.13(BN26) rats. Renal interstitial administration of Etanercept, an inhibitor of TNFα, significantly attenuated the development of hypertension in SS rats on a high-salt diet (n = 7-8, p < 0.05). Glomerulosclerosis and interstitial fibrosis were also significantly ameliorated. These findings indicate intrarenal TNFα contributes to the development of hypertension and renal injury in SS rats.

SUBMITTER: Huang B

PROVIDER: S-EPMC4768148 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Salt-Sensitive Hypertension, Renal Injury, and Renal Vasodysfunction Associated With Dahl Salt-Sensitive Rats Are Abolished in Consomic SS.BN1 Rats.

Project description:Background Abnormal renal hemodynamic responses to salt-loading are thought to contribute to salt-sensitive (SS) hypertension. However, this is based largely on studies in anesthetized animals, and little data are available in conscious SS and salt-resistant rats. Methods and Results We assessed arterial blood pressure, renal function, and renal blood flow during administration of a 0.4% NaCl and a high-salt (4.0% NaCl) diet in conscious, chronically instrumented 10- to 14-week-old Dahl SS and consomic SS rats in which chromosome 1 from the salt-resistant Brown-Norway strain was introgressed into the genome of the SS strain (SS.BN1). Three weeks of high salt intake significantly increased blood pressure (20%) and exacerbated renal injury in SS rats. In contrast, the increase in blood pressure (5%) was similarly attenuated in Brown-Norway and SS.BN1 rats, and both strains were completely protected against renal injury. In SS.BN1 rats, 1 week of high salt intake was associated with a significant decrease in renal vascular resistance (-8%) and increase in renal blood flow (15%). In contrast, renal vascular resistance failed to decrease, and renal blood flow remained unchanged in SS rats during high salt intake. Finally, urinary sodium excretion and glomerular filtration rate were similar between SS and SS.BN1 rats during 0.4% NaCl and high salt intake. Conclusions Our data support the concept that renal vasodysfunction contributes to blood pressure salt sensitivity in Dahl SS rats, and that genes on rat chromosome 1 play a major role in modulating renal hemodynamic responses to salt loading and salt-induced hypertension.

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(-)-Epigallocatechin-3-gallate (EGCG) attenuates salt-induced hypertension and renal injury in Dahl salt-sensitive rats.

Project description:Epigallocatechin-3-gallate (EGCG), a main active catechin in green tea, was reported to attenuate renal injury and hypertension. However, its effects on salt-induced hypertension and renal injury remain unclear. In the present study, we explored its effects on hypertension and renal damage in Dahl rats with salt-sensitive hypertension. We found that EGCG could lower blood pressure after 6 weeks of oral administration, reduce 24 h urine protein levels and decrease creatinine clearance, and attenuate renal fibrosis, indicating that it could attenuate hypertension by protecting against renal damage. Furthermore, we studied the renal protective mechanisms of EGCG, revealing that it could lower malondialdehyde levels, reduce the numbers of infiltrated macrophages and T cells, and induce the apoptosis of NRK-49F cells. Considering that the 67 kD laminin receptor (67LR) binds to EGCG, its role in EGCG-induced fibroblast apoptosis was also investigated. The results showed that an anti-67LR antibody partially abrogated the apoptosis-inducing effects of EGCG on NRK-49F cells. In summary, EGCG may attenuate renal damage and salt-sensitive hypertension via exerting anti-oxidant, anti-inflammatory, and apoptosis-inducing effects on fibroblasts; the last effect is partially mediated by 67LR, suggesting that EGCG represents a potential strategy for treating salt-sensitive hypertension.

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Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage.

Project description:Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc finger nuclease targeting bases 672-706 of recombination-activating gene 1 (Rag1) was injected into the pronucleus of Dahl SS (SS/JrHsdMcwi) strain embryos and implanted in pseudopregnant females. This strategy yielded a rat strain with a 13-base frame-shift mutation in the target region of Rag1 and a deletion of immunoreactive Rag1 protein in the thymus. Flow cytometry demonstrated that the Rag1-null mutant rats have a significant reduction in T and B lymphocytes in the circulation and spleen. Studies were performed on SS and Rag1-null rats fed a 4.0% NaCl diet for 3 wk. The infiltration of T cells into the kidney following high-salt intake was significantly blunted in the Rag1-null rats (1.7 ± 0.6 × 10(5) cells/kidney) compared with the Dahl SS (5.6 ± 0.9 × 10(5) cells/kidney). Accompanying the reduction in infiltration of immune cells in the kidney, mean arterial blood pressure and urinary albumin excretion rate were significantly lower in Rag1-null mutants (158 ± 3 mmHg and 60 ± 16 mg/day, respectively) than in SS rats (180 ± 11 mmHg and 251 ± 37 mg/day). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the SS rats fed a high-salt diet was also attenuated in the Rag1 mutants. These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats.

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High Fructose-Induced Hypertension and Renal Damage Are Exaggerated in Dahl Salt-Sensitive Rats via Renal Renin-Angiotensin System Activation.

Project description:Background High-fructose diet (HFr) induces hypertension and renal damage. However, it has been unknown whether the HFr-induced hypertension and renal damage are exaggerated in subjects with salt sensitivity. We tested impacts of HFr in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. Methods and Results Male DS and DR rats were fed control diet or HFr (60% fructose) with normal-salt content. After 12 weeks, plasma and urinary parameters, renal histological characteristics, and renal expression of renin-angiotensin system components were examined. Furthermore, effects of renin-angiotensin system inhibitors were also examined in DS rats fed the HFr. HFr elevated blood pressure in DS rats but not in DR rats. HFr increased urinary albumin and liver type fatty acid binding protein excretions in both rats, but the excretions were exaggerated in DS rats. HFr increased plasma lipids and uric acid in both rats, whereas HFr increased creatinine clearance in DS rats but not DR rats. Although HFr decreased plasma renin activity in DS rats, HFr-induced glomerular injury, afferent arteriolar thickening, and renal interstitial fibrosis were exaggerated in DS rats. HFr increased renal expression of angiotensinogen, renin, (pro)renin receptor, angiotensin-converting enzyme, and angiotensin II type 1 receptor in DS rat, whereas HFr increased only angiotensin-converting enzyme expression and decreased renin and angiotensin II type 1 receptor expressions in DR rats. Enalapril and candesartan attenuated the HFr-induced hypertension, albuminuria, glomerular hyperfiltration, and renal damage in DS rats. Conclusion HFr-induced hypertension and renal damage are exaggerated in DS rats via renal renin-angiotensin system activation, which can be controlled by renin-angiotensin system inhibitors.

| S-EPMC8483472 | biostudies-literature

Maternal diet during gestation and lactation modifies the severity of salt-induced hypertension and renal injury in Dahl salt-sensitive rats.

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Activated pathogenic Th17 lymphocytes induce hypertension following high-fructose intake in Dahl salt-sensitive but not Dahl salt-resistant rats.

Project description:High-salt intake and high-fructose intake are risk factors for hypertension via oxidative stress and inflammation. T helper (Th)17 lymphocytes play an important role in the development of hypertension. Here, we tested the hypothesis that activation of pathogenic Th17 lymphocytes induces hypertension after high-fructose intake in Dahl salt-sensitive (SS) but not Dahl salt-resistant (SR) rats. Eight-week-old male SS and SR rats were offered 20% fructose solution or tap water only for 4 weeks. Systolic blood pressure was measured by the tail-cuff method. T lymphocyte [Th17 and T regulatory (Treg)] profiling was determined via flow cytometry. The expression of Th17-related (IL-17A, IL-17RA, IL-23R and RORγt) and Treg-related (IL-10, CD25, FOXP3 and TGFβ) factors were measured via ELISA or qRT-PCR. Th17 lymphocytes isolated from high-fructose-fed SS rats were intraperitoneally injected into recipient SS and SR rats, and recombinant IL-23 protein was subcutaneously injected into SS and SR rats to induce hypertension.High-fructose intake induced hypertension via the activation of pathogenic Th17 lymphocytes in SS but not SR rats. Injection of activated Th17 lymphocytes isolated from fructose-fed SS rats induced hypertension via increase of serum IL-17A only in recipient SS rats. In addition, injection of IL-23 induced hypertension via activation of pathogenic Th17 lymphocytes only in SS rats.Thus, activation of pathogenic Th17 lymphocytes induces hypertension after high-fructose intake in SS but not SR rats. These results indicate that immunologic tolerance plays an important role in protection against hypertension in SR rats.

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Renal medullary 11 beta-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension.

Project description:The Dahl salt-sensitive rat is a widely used model of human salt-sensitive forms of hypertension. The kidney plays an important role in the pathogenesis of Dahl salt-sensitive hypertension, but the molecular mechanisms involved remain a subject of intensive investigation. Gene expression profiling studies suggested that 11 beta-hydroxysteroid dehydrogenase type 1 might be dysregulated in the renal medulla of Dahl salt-sensitive rats. Additional analysis confirmed that renal medullary expression of 11 beta-hydroxysteroid dehydrogenase type 1 was downregulated by a high-salt diet in SS-13BN rats, a consomic rat strain with reduced blood pressure salt sensitivity, but not in Dahl salt-sensitive rats. 11 beta-Hydroxysteroid dehydrogenase type 1 is known to convert inactive 11-dehydrocorticosterone to active corticosterone. The urinary corticosterone/11-dehydrocorticosterone ratio as well as urinary excretion of corticosterone was higher in Dahl salt-sensitive rats than in SS-13BN rats. Knockdown of renal medullary 11 beta-hydroxysteroid dehydrogenase type 1 with small-interfering RNA attenuated the early phase of salt-induced hypertension in Dahl salt-sensitive rats and reduced urinary excretion of corticosterone. Knockdown of 11 beta-hydroxysteroid dehydrogenase type 1 did not affect blood pressure in SS-13BN rats. Long-term attenuation of salt-induced hypertension was achieved with small hairpin RNA targeting renal medullary 11 beta-hydroxysteroid dehydrogenase type 1. In summary, we have demonstrated that suppression of 11 beta-hydroxysteroid dehydrogenase type 1 expression in the renal medulla attenuates salt-induced hypertension in Dahl salt-sensitive rats.

| S-EPMC2604787 | biostudies-literature

Insights into Dahl salt-sensitive hypertension revealed

Project description:The results of this study identified a number of pathways potentially important for the amelioration of hypertension and renal injury in SS-13BN/Mcw rats, and these results generated a series of testable hypotheses related to the role of the renal medulla in the complex mechanism of salt-sensitive hypertension. Keywords: time course, microarray; 11ß-hydroxysteroid dehydrogenase; glucagon receptor; extracellular matrix; apoptosis

2005-11-17 | GSE3588 | GEO

Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.

Project description:In response to high salt intake, transcription factor hypoxia-inducible factor (HIF) 1? activates many antihypertensive genes, such as heme oxygenase 1 (HO-1) 1 and cyclooxygenase 2 (COX-2) in the renal medulla, which is an important molecular adaptation to promote extra sodium excretion. We recently showed that high salt inhibited the expression of HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1?, thereby upregulating HIF-1?, and that high salt-induced inhibition in PHD2 and subsequent activation of HIF-1? in the renal medulla was blunted in Dahl salt-sensitive hypertensive rats. This study tested the hypothesis that silencing the PHD2 gene to increase HIF-1? levels in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats.PHD2 short hairpin RNA (shRNA) plasmids were transfected into the renal medulla in uninephrectomized Dahl S rats. Renal function and blood pressure were then measured.PHD2 shRNA reduced PHD2 levels by >60% and significantly increased HIF-1? protein levels and the expression of HIF-1? target genes HO-1 and COX-2 by >3-fold in the renal medulla. Functionally, pressure natriuresis was remarkably enhanced, urinary sodium excretion was doubled after acute intravenous sodium loading, and chronic high salt-induced sodium retention was remarkably decreased, and as a result, salt-sensitive hypertension was significantly attenuated in PHD2 shRNA rats compared with control rats.Impaired PHD2 response to high salt intake in the renal medulla may represent a novel mechanism for hypertension in Dahl S rats, and inhibition of PHD2 in the renal medulla could be a therapeutic approach for salt-sensitive hypertension.

| S-EPMC3848632 | biostudies-literature

Kidneys of Dahl salt sensitive rats

Project description:Gene expression profiling of kidney tissue from 5 week old Dahl salt sensitive rats and congenic strain of Chr.10 Dahl salt sensitive rats. Keywords: other

2003-08-20 | GSE413 | GEO

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