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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.

ABSTRACT: 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.

SUBMITTER: Potter JC

PROVIDER: S-EPMC8751849 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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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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Analysis of metabolites in plasma reveals distinct metabolic features between Dahl salt-sensitive rats and consomic SS.13(BN) rats.

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Sex Differences in Renal Inflammation and Injury in High-Fat Diet-Fed Dahl Salt-Sensitive Rats.

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

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| S-EPMC3602820 | biostudies-literature

Loss of <i>Arhgef11</i> in the Dahl Salt-Sensitive Rat Protects Against Hypertension-Induced Renal Injury.

Project description:Arhgef11 is a Rho-guanine nucleotide exchange factor that was previously implicated in kidney injury in the Dahl salt-sensitive (SS) rat, a model of hypertension-related chronic kidney disease. Reduced Arhgef11 expression in an SS-Arhgef11SHR-minimal congenic strain (spontaneously hypertensive rat allele substituted for S allele) significantly decreased proteinuria, fibrosis, and improved renal hemodynamics, without impacting blood pressure compared with the control SS (SS-wild type). Here, SS-Arhgef11-/- and SS-wild type rats were placed on either low or elevated salt (0.3% or 2% NaCl) from 4 to 12 weeks of age. On low salt, starting at week 6 and through week 12, SS-Arhgef11-/- animals demonstrated a 3-fold decrease in proteinuria compared with SS-wild type. On high salt, beginning at week 6, SS-Arhgef11-/- animals demonstrated >2-fold lower proteinuria from weeks 8 to 12 and 30 mm Hg lower BP compared with SS-wild type. To better understand the molecular mechanisms of the renal protection from loss of Arhgef11, both RNA sequencing and discovery proteomics were performed on kidneys from week 4 (before onset of renal injury/proteinuria between groups) and at week 12 (low salt). The omics data sets revealed loss of Arhgef11 (SS-Arhgef11-/-) initiates early transcriptome/protein changes in the cytoskeleton starting as early as week 4 that impact a number of cellular functions, including actin cytoskeletal regulation, mitochondrial metabolism, and solute carrier transporters. In summary, in vivo phenotyping coupled with a multi-omics approach provides strong evidence that increased Arhgef11 expression in the Dahl SS rat leads to actin cytoskeleton-mediated changes in cell morphology and cell function that promote kidney injury, hypertension, and decline in kidney function.

| S-EPMC8167818 | biostudies-literature

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

Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats.

Project description:The goal of the present study was to explore the protective effects of mTORC1 (mammalian target of rapamycin complex 1) inhibition by rapamycin on salt-induced hypertension and kidney injury in Dahl salt-sensitive (SS) rats. We have previously demonstrated that H2O2 is elevated in the kidneys of SS rats. The present study showed a significant upregulation of renal mTORC1 activity in the SS rats fed a 4.0% NaCl for 3 days. In addition, renal interstitial infusion of H2O2 into salt-resistant Sprague Dawley rats for 3 days was also found to stimulate mTORC1 activity independent of a rise of arterial blood pressure. Together, these data indicate that the salt-induced increases of renal H2O2 in SS rats activated the mTORC1 pathway. Daily administration of rapamycin (IP, 1.5 mg/kg per day) for 21 days reduced salt-induced hypertension from 176.0±9.0 to 153.0±12.0 mm Hg in SS rats but had no effect on blood pressure salt sensitivity in Sprague Dawley treated rats. Compared with vehicle, rapamycin reduced albumin excretion rate in SS rats from 190.0±35.0 to 37.0±5.0 mg/d and reduced the renal infiltration of T lymphocytes (CD3+) and macrophages (ED1+) in the cortex and medulla. Renal hypertrophy and cell proliferation were also reduced in rapamycin-treated SS rats. We conclude that enhancement of intrarenal H2O2 with a 4.0% NaCl diet stimulates the mTORC1 pathway that is necessary for the full development of the salt-induced hypertension and kidney injury in the SS rat.

| S-EPMC5599353 | biostudies-literature

Amelioration of cardio-renal injury with aging in dahl salt-sensitive rats by H2-enriched electrolyzed water.

Project description:UnlabelledRecent studies have revealed the biological effects of H2 in suppressing organ injuries due to acute inflammation and oxidative stress. Dahl salt-sensitive (SS) rats naturally develop elevated blood pressure (BP) and kidney injury with aging. The present study examined the effect of long-term supplementation of H2 in drinking water on age-related changes.Four-week-old male Dahl SS rats were fed 3 types of water (n?=?30 each) for up to 48 weeks: filtered water (FW), water with a high H2 content (492.5 ppb) obtained with water electrolysis (EW), or dehydrogenated EW (DW). Animals were subjected to histological analysis at 16, 24, and 48 weeks.The FW group showed progressive BP elevation and increases in albuminuria and cardiac remodeling during the course of treatment. Histologically, there were significant changes as a function of aging, i.e., glomerular sclerosis with tubulointerstitial fibrosis in the kidney, and increased cardiomyocyte diameter with interstitial fibrosis in the heart at 48 weeks. These changes were related to the enhanced inflammation and oxidative stress in the respective organs. However, there were no striking differences in BP among the groups, despite histological alterations in the EW group being significantly decreased when compared to FW and DW in both organs, with concurrently lower oxidative stress and inflammatory markers at 48 weeks.ConclusionLong-term ad libitum consumption of H2-enriched electrolyzed water can ameliorate the processes of kidney injury and cardiac remodeling with aging in Dahl SS rats by suppressing, at least partly, elevated inflammation and oxidative stress.

| S-EPMC3866609 | biostudies-literature

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