Increased dietary salt accelerates chronic allograft nephropathy in rats

Sanders, Paul W.; Gibbs, Cari L.; Akhi, Kabir M.; MacMillan-Crow, Lee Ann; Zinn, Kurt R.; Chen, Yiu-Fai; Young, Carlton J.; Thompson, John A.

doi:10.1046/j.1523-1755.2001.0590031149.x

Cited by 32 publications

(14 citation statements)

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“…31 The present results are compatible with previous descriptions of age-related kidney changes and with the sexual dimorphism pattern of these morphological features. 30,31 Our data also reveal more intense histopathologic tubulointerstitial renal lesions and a higher degree of interstitial fibrosis in both UNX groups versus controls and in the male versus female UNX rats.…”

Section: Discussionsupporting

confidence: 56%

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Long-Term Consequences of Uninephrectomy in Male and Female Rats

et al. 2012

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Abstract-We investigated the effects of uninephrectomy (UNX) in 6-week-old male and female rats on blood pressure (BP), renal sodium handling, salt sensitivity, oxidative stress, and renal injury over 18 months postsurgery, studying control sham-operated and UNX-operated rats at 6, 12, and 18 months postsurgery, evaluating their renal sodium handling, BP, urinary isoprostanes, N-acetyl-β-d-glucosaminidase, and proteinuria before and after a 2-week high-salt intake period. At 18 months, plasma variables were measured and kidney samples were taken for the analysis of renal morphology and tissue variables. BP was increased at 6 months in male UNX rats versus controls and at 12 and 18 months in both male and female UNX rats and was increased in male versus female UNX groups at 18 months. UNX did not affect water and sodium excretion under basal conditions and after the different test in male and female rats at different ages. However, the renal function curve was shifted to the right in both male and female UNX rats. Highsalt intake increased BP in both UNX groups at 6, 12, and 18 months and in the female control group at 18 months, and it increased proteinuria, N-acetyl-β-d-glucosaminidase, and isoprostanes in both UNX groups throughout the study. Renal lesions at 18 months were more severe in male versus female UNX rats. In summary, long-term UNX increased the BP, creatinine, proteinuria, pathological signs of renal injury, and salt sensitivity. Earlier BP elevation was observed and morphological lesions were more severe in male than in female UNX rats. Rodríguez-Gómez et al Effects of Uninephrectomy in Rats 1459scarcely more feasible to recruit living donors for the longterm follow-up of key renal functional and morphological parameters. With this background, the objective of the present study was to examine the consequences of UNX in male and female rats, as a model of donor nephrectomy, on BP, renal sodium handling, salt sensitivity, oxidative stress, and renal injury over 18 months and on renal pathology variables gathered at 18 months. Methods AnimalsMale and female Wistar rats born and raised in the experimental animal service of the University of Granada were used. Experiments were performed according to European Union guidelines for the ethical care of animals. At 6 weeks of age, the rats were divided into 4 groups (n=25 in each), 1 male and 1 female group for UNX and 1 male and 1 female group for sham operation (controls). In the UNX group, total extirpation of the left kidney was performed, leaving the adrenal gland intact. Sham-operated animals were prepared in the same manner, and the left kidney was handled but not removed. Postsurgery, all animals had access to standard chow and tap water ad libitum. Experimental ProtocolThe same experimental protocol was repeated in the same 8 rats from each study group at 6, 12, and 18 months after surgery in the following consecutive procedures: (1) for baseline, animals were housed in metabolic cages (Panlab, Barcelona, Spain) with food and tap water available ...

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Section: Discussionsupporting

confidence: 56%

“…30,31 The normal aging process leads to slightly more pronounced changes in kidney morphology in male versus female rats. 31 Old intact male rats develop glomerulosclerosis, but castrated male rats are protected from this injury.…”

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confidence: 99%

Long-Term Consequences of Uninephrectomy in Male and Female Rats

et al. 2012

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“…Early and longterm exposure of rats to a high-sodium diet may explain the decrease in GFR and enhanced albuminuria through an increase in TGF-␤ 1 production (23). Although feeding adult Lewis rats for 13 wk with a high-sodium diet did not have an effect on blood pressure and renal histology (mainly no mesangial expansion), moderate albuminuria did develop (15), thus suggesting that albuminuria may precede consistent renal structural changes. Of interest, GFR and filtration fraction returned to values similar to normal animals, whereas resistance of excessive albuminuria to spironolactone was observed.…”

Section: Discussionmentioning

confidence: 90%

Cardiorenal abnormalities associated with high sodium intake: correction by spironolactone in rats

Cordaillat

Rugale

Casellas

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Cordaillat, Magali, Caroline Rugale, Daniel Casellas, Albert Mimran, and Bernard Jover. Cardiorenal abnormalities associated with high sodium intake: correction by spironolactone in rats. Am J Physiol Regul Integr Comp Physiol 289: R1137-R1143, 2005. First published May 26, 2005; doi:10.1152/ajpregu.00154.2005.-Reversal by the mineralocorticoid receptor antagonist spironolactone on cardiac and renal abnormalities, associated with long-term (since weaning) administration of a high (2 and 8% NaCl chow, HS2 and HS8) sodium diet, was assessed in Sprague-Dawley rats. At the age of 5 mo, spironolactone (20 or 100 mg/kg, gavage) or placebo were given for 14 days to HS2 and HS8 rats. A group fed a regular diet (0.8% NaCl, NS) remained untreated. High sodium intake had no detectable effect on blood pressure; however, cardiac mass index and cross-sectional area of the carotid artery, as well as albuminuria, were increased only in the HS8 group compared with the control group on NS diet. In addition, a marked reduction in glomerular filtration rate (by 40%), associated with a nonproportional fall in renal plasma flow (thus resulting in a decrease in filtration fraction), was observed only in the HS8 group. No change in cardiac and renal fibrosis was detected. Production of the reactive oxygen species (ROS) by aortic tissue was increased in HS8 rats, whereas ROS production by the heart was unaffected. Only the high dose of spironolactone was effective, as it markedly reversed the cardiac hypertrophy and renal hypofiltration associated with the HS8 feeding. The changes were observed in the absence of any effect on systemic blood pressure and production of ROS. These observations favor aldosterone's role in the deleterious effects of marked and prolonged increases in sodium intake. spironolactone; renal function; reactive oxygen species; cardiac hypertrophy IN ADDITION TO ITS WIDELY debated effect on blood pressure, chronic variation of sodium intake has been reported to modulate the cardiovascular morphology in human and experimental models. In animal studies, dietary sodium restriction has been shown to prevent the development of cardiac hypertrophy in renovascular (13) and ANG II-induced hypertension (14), independently of blood pressure. Reversal of cardiac hypertrophy was achieved by 6 wk on a low-sodium diet in 2-kidney, one-clip hypertensive rats (17). Administration of a diet containing 8% sodium chloride for more than 4 wk was associated with the development of left ventricular hypertrophy, cardiac fibrosis, and an increase in collagen content (10,23).Because an increase in systemic pressure associated with high sodium was not consistently observed, it was suggested that a direct effect of sodium may underlie the increased sensitivity of target organs to blood pressure. Interestingly, in a cohort of normotensive subjects and never-treated patients with essential hypertension, it was recently demonstrated that increasing dietary sodium (as estimated by 24-h natriuresis), enhanced the slope of the relationship between...

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“…In another study, administration of 8.0% NaCl diet to Fisher/Lewis rats after orthotopic renal transplantation accelerated the development of chronic allograft nephropathy. An increase in tubulointerstitial fibrosis and glomerular sclerosis was demonstrated; 68 an associated increase in urinary excretion rate and renal cortical levels of TGF-␤1 was also observed (unpublished observations from this laboratory, 2001).…”

Section: Importance Of Salt Intake In the Progression Of Chronic Kidnmentioning

confidence: 84%

Salt Intake, Endothelial Cell Signaling, and Progression of Kidney Disease

Sanders

2004

Hypertension

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Abstract-It has been known for decades that increased dietary intake of salt (NaCl) shortens the life span of rats in a dose-dependent fashion. This review focuses specifically on the recently described biological effect and consequences of increased salt ingestion on the endothelium through a mechanism that is independent of blood pressure. Changes in salt intake are recognized by endothelial cells in the vascular tree and glomeruli through a physical process that promotes a series of signaling events involved in transcriptional regulation of genes that include transforming growth factor-␤1 (TGF-␤1) and the endothelial isoform of nitric oxide synthase (NOS3). A balance is struck between TGF-␤1 and NOS3 as salt intake varies and creates a negative feedback loop, because TGF-␤1 increased expression of NOS3 and NO inhibited production of TGF-␤1 in healthy rats. Changes in this feedback system have been observed in salt-sensitive hypertension and appear to impact end-organ damage, particularly the kidney. The data support an important benefit to reduction of salt intake in the setting of chronic kidney disease. Key Words: endothelium Ⅲ vascular disease Ⅲ nitric oxide Ⅲ gene expression Ⅲ hypertension T he Guyton hypothesis 1,2 regarding the relationship between salt balance and blood pressure continues to be a focus of intense research activity, in part related to the discovery of the association between genetic defects in renal sodium handling and hypertension. There are several excellent reviews of this subject. [3][4][5] Recent studies demonstrating that the endothelium responds to changes in salt intake through a mechanism that is independent of blood pressure, however, have challenged the sole emphasis of the effect of salt intake on blood pressure regulation. This brief review focuses on the important role of the endothelium as a biomechanical sensor that detects changes in dietary salt intake in physiological and pathophysiological states. Transforming Growth Factor-␤ and Salt IntakeFor physicians and scientists interested in progressive kidney disease, perhaps the most important growth factor yet identified is transforming growth factor-␤ (TGF-␤). After the discovery of TGF-␤ in 1980, 6 numerous studies have shown that this fibrogenic or prosclerotic growth factor participates integrally in renal fibrosis in a variety of disease states. Several years ago, this laboratory became interested in the role of TGF-␤ in generation of hypertensive nephrosclerosis, but early experiments demonstrated that dietary salt produced an increase in steady-state mRNA levels of TGF-␤1 in the kidney cortex of Sprague-Dawley rats; the effect occurred without a change in blood pressure and developed within 1 day of the increase in salt intake and persisted over the course of the experiment. 31 Increasing salt intake also promoted an increase in production of TGF-␤1 from aortic ring preparations; the effect was lost after removal of the endothelium. 32 These studies provided direct evidence that the endothelium responded to change...

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Increased dietary salt accelerates chronic allograft nephropathy in rats

Abstract: In this model of CAN, renal allograft dysfunction preceded hypertension and was accelerated significantly by an increase in dietary salt.

Cited by 32 publications

References 20 publications

Long-Term Consequences of Uninephrectomy in Male and Female Rats

Long-Term Consequences of Uninephrectomy in Male and Female Rats

Cardiorenal abnormalities associated with high sodium intake: correction by spironolactone in rats

Salt Intake, Endothelial Cell Signaling, and Progression of Kidney Disease

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