Renal functional, not morphological, abnormalities account for salt sensitivity in Dahl rats

Manger, William M.; Simchon, Shlomoh; Stokes, Michael B.; Reidy, Jason J; Kumar, Asok; Baer, Leslie; Gallo, Gloria; Haddy, Francis J.

doi:10.1097/hjh.0b013e32831ffec7

Cited by 6 publications

(4 citation statements)

References 44 publications

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“…Aldosterone, acting through the mineralocorticoid receptor, is a major regulator of ENaC. While studies in the early 1990s showed lower levels for plasma aldosterone in S vs. R (Cover et al 1995), recent studies show similar or higher levels in S rats (Manger et al 2009;Takeda et al 2007). Plasma aldosterone concentration decreased with high salt in both strains, consistent with previous studies (Aoi et al 2007;Farjah et al 2003;Zhu et al 2009), but remained somewhat higher in S. This suggests a similar regulation of plasma aldosterone by high salt.…”

Section: Regulators Of Renal Enacsupporting

confidence: 81%

Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats

Amin

Reza

El-Shahat

et al. 2011

Can. J. Physiol. Pharmacol.

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Inner medullary collecting duct (IMCD) cells from salt-sensitive (S) Dahl rats transport twice as much Na(+) as cells from salt-resistant (R) rats, possibly related to dysregulation of the renal epithelial sodium channel (ENaC). The effect of a high-salt diet on ENaC expression in the inner medulla of S versus R rats has not yet been studied. Young, male S and R rats were placed on a regular-salt (0.3%) or high-salt (8%) diet for 2 or 4 weeks. mRNA and protein expression of ENaC subunits were studied by real-time PCR and immunoblotting. Intracellular distribution of the subunits in the IMCD was evaluated by immunohistochemistry. On regular salt, the abundance of the mRNA of β and γENaC was higher in the medulla of S rats than R rats. This was associated with a greater protein abundance of 90 kDa γENaC and higher immunoreactivity for both α and γ ENaC. High salt did not affect mRNA abundance in either strain and decreased apical staining of βENaC in IMCD of R rats. In contrast, high salt did not affect the higher apical localization of αENaC and increased the apical membrane staining for β and γENaC in the IMCD of S rats. Expression of ENaC subunits is enhanced in the medulla of S vs. R rats on regular salt, and further increased on high salt. The persistent high expression of αENaC and increase in apical localization of β and γENaC may contribute to greater retention of sodium in S rats on a high-salt diet.

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Section: Regulators Of Renal Enacsupporting

confidence: 81%

Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats

Amin

Reza

El-Shahat

et al. 2011

Can. J. Physiol. Pharmacol.

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“…This system may be blunted by RSV treatment [22], [31] thus reducing the cardiac hypertrophy. In contrast, in DSS rats, circulating RAS is rather inhibited [32] and hypertension is mostly linked to blood volume expansion [33] so that potential anti-RAS activity of RSV does not reduce hypertension. This suggests that resveratrol may have separate, beneficial effects on hypertension and cardiac hypertrophy, and thus the benefits of resveratrol may depend on the etiology of HF.…”

Section: Discussionmentioning

confidence: 89%

Resveratrol Improves Survival, Hemodynamics and Energetics in a Rat Model of Hypertension Leading to Heart Failure

et al. 2011

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Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001), and prevented the 25% reduction in body weight in HS-NT (P<0.001). Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening −34% in HS-NT) as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium–dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF.

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“…Fourth, this model is especially good for studying renal disease. Functional abnormalities in the kidneys account for salt sensitivity and hypertension, not hypertension‐induced renal damage . Furthermore, Dahl‐S rats develop a progressive decline in glomerular filtration rate as a consequence of hypertension .…”

Section: Discussionmentioning

confidence: 99%

Antihypertensive and anti‐inflammatory actions of combined azilsartan and chlorthalidone in Dahl salt‐sensitive rats on a high‐fat, high‐salt diet

Jin

O'Boyle

Kleven

et al. 2014

Clin Exp Pharma Physio

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Metabolic syndrome (MetS) and chronic kidney disease are global health issues. Metabolic syndrome induces hypertension and commonly results in renal damage. The optimal therapy for hypertension in MetS is unknown. Thiazide diuretics are first-line therapy; however, these drugs may have untoward effects. In the present study we investigated the effects of azilsartan (AZL), chlorthalidone (CLTD) and their combination on blood pressure and renal injury in a rodent model with features of MetS. Dahl salt-sensitive rats were fed high-fat (36% fat), high-salt (4% NaCl) diet. Groups were then treated with vehicle, AZL (3 mg/kg per day), CLTD (5 mg/kg per day) or AZL + CLTD. Mean arterial pressure was recorded continuously by telemetry. After 26 days, rats were killed humanely and their kidneys were harvested for histology. Both AZL and CLTD attenuated the rise in blood pressure compared with vehicle and the combination further reduced blood pressure compared with CLTD alone. All treatments reduced proteinuria and albuminuria. Nephrinuria was prevented only in groups treated with AZL. Nephrinuria was 57% lower and proteinuria was 47% lower with combination therapy compared with AZL alone. All treatments reduced the number of inflammatory cells in the kidney. In conclusion, in our model, AZL and CLTD lower blood pressure and exhibit renal protective effects. Treatment with AZL offers additional protection, as evidenced by lower nephrinuria and plasma monocyte chemoattractant protein-1 levels. Combination therapy afforded the greatest protective effects and may be the best choice for hypertensive therapy in MetS.

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Renal functional, not morphological, abnormalities account for salt sensitivity in Dahl rats

Abstract: We conclude that renal functional, not morphological, abnormalities cause salt sensitivity in Dahl rats.

Cited by 6 publications

References 44 publications

Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats

Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats

Resveratrol Improves Survival, Hemodynamics and Energetics in a Rat Model of Hypertension Leading to Heart Failure

Antihypertensive and anti‐inflammatory actions of combined azilsartan and chlorthalidone in Dahl salt‐sensitive rats on a high‐fat, high‐salt diet

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