Porcine Salmonellosis

Renal vascular lesions associated with experimentally induced septicemic porcine salmonellosis consisted of fibrinoid necrosis of the vessel walls and fibrin thrombi within the lumina of interlobular arteries, afferent arterioles and glomerular capillary loops. Extrarenal vascular alterations were predominantly localized to the skin and the lungs. In these sites, too, mere fibrin thrombi were found in the capillaries, whereas mixed thrombi, consisting of fibrin, platelets, leucocytes and erythrocytes were present in larger vessels. The conclusion is drawn that the renal vascular injury is completely compatible to the generalized Shwartzman reaction, while the extrarenal vascular changes may only in part depend on this mechanism.     

Regression of Glomerular and Tubulointerstitial Injuries by Dietary Salt Reduction with Combination Therapy of Angiotensin II Receptor Blocker and Calcium Channel Blocker in Dahl Salt-Sensitive Rats

A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.     

Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension

Renal immune cell infiltration and cells expressing angiotensin II (AII) in tubulointerstitial areas of the kidney are features of experimental models of salt-sensitive hypertension (SSHTN). A high-salt intake tends to suppress circulating AII levels, but intrarenal concentrations of AII have not been investigated in SSHTN. This study explored the relationship between these features to gain insight into the pathophysiology of SSHTN. Plasma angiotensin II (AII) and renal interstitial AII (microdialysis technique) and the infiltration of macrophages, lymphocytes, and AII-positive cells were determined in SSHTN induced by 5 wk of a high-salt diet (HSD) after short-term infusion of AII in rats with (n = 10) and without (n = 11) treatment with mycophenolate mofetil (MMF) and in control rats fed a high- (n = 7) and normal (n = 11) salt diet. As in previous studies, MMF did not affect AII-associated hypertension but reduced the interstitial inflammation and the SSHTN in the post-AII-period. During the HSD period, the AII group untreated with MMF had mean +/- SD) low plasma (2.4 +/- 1.4 pg/ml) and high interstitial AII concentration (1,310 +/- 208 pg/ml); MMF treatment resulted in a significantly lower interstitial AII (454 +/- 128 pg/ml). Renal AII concentration and the number of tubulointerstitial AII-positive cells were correlated. Blood pressure correlated positively with interstitial AII and negatively with plasma AII, thus giving compelling evidence of the paramount role of the AII within the kidney in the AII-induced model of salt-driven hypertension.     

Effects of high salt intake on brain AT1 receptor densities in Dahl rats

To assess effects of dietary salt on brain AT1 receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 mumol Na/g) or high (1,370 mumol Na/g)-salt diet for 1, 2, or 4 wk. AT1 receptors were assessed by quantitative in vitro autoradiography. AT1 receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased AT1 receptor binding by 21-64% in the Dahl S rats in the subfornical organ, median preoptic nucleus, paraventricular nucleus, and suprachiasmatic nucleus. No changes were noted in the Dahl R rats. After 4 wk on a high-salt diet, increases in AT1 receptor binding persisted in Dahl S rats but were now also noted in the paraventricular nucleus, median preoptic nucleus, and suprachiasmatic nucleus of Dahl R rats. At 4 wk on the diet, intracerebroventricular captopril caused clear decreases in blood pressure only in the Dahl S on the high-salt diet but caused largely similar relative increases in brain AT1 receptor densities in Dahl S and R on the high-salt diet versus regular salt diet. These data demonstrate that high salt intake rapidly (within 1 wk) increases AT1 receptor densities in specific brain nuclei in Dahl S and later (by 4 wk) also in Dahl R rats. Because the brain renin-angiotensin system only contributes to salt-induced hypertension in Dahl S rats, further studies are needed to determine which of the salt-induced increases in brain AT1 receptor densities contribute to the hypertension and which to other aspects of body homeostasis.     

Effect of saline infusion on kidney and collecting duct function in atrial natriuretic peptide (ANP) gene "knockout" mice.

Atrial natriuretic peptide (ANP) is thought to play a role in renal regulation of salt balance by reducing tubular reabsorption of sodium and chloride. Therefore, in the chronic absence of this hormone, a defect of salt excretion should be evident. We used an ANP gene deletion model to test this premise. F2 homozygous mutant mice (-/-) and their wild-type littermates (+/+) were fed an 8% NaCl diet prior to an acute infusion of isotonic saline. Arterial blood pressures, renal excretions of salt and water, as well as collecting duct transport of fluid and electrolytes were measured. Pressures were significantly higher in -/- compared with +/+ mice (139 +/- 4 vs. 101 +/- 2 mmHg; 1 mmHg = 133.3 Pa). There was no difference in glomerular filtration rate (-/- = 0.84 +/- 0.06; +/+ = 0.81 +/- 0.04 mL x min(-1) x g(-1) kidney weight). In the collecting duct, sodium and chloride reabsorptions were significantly higher in the -/- group than in the +/+ group. As a result, natriuresis and chloruresis were relatively reduced (U(Na)V: -/- = 8.6 +/- 1.1; +/+ = 14.0 +/- 1.1; U(Cl)V: -/- = 10.1 +/- 1.4; +/+ = 16.0 +/- 1.1 micromol x min(-1) x g(-1) kidney weight). We conclude that the absence of endogenous ANP activity in mice on a high-salt diet subjected to acute saline infusion causes inappropriately high reabsorption of sodium and chloride in the medullary collecting duct, resulting in a relative defect in renal excretory capacity for salt.     

Elucidating mechanisms underlying altered renal autoregulation in diabetes

Previous studies have reported that high-salt intake paradoxically activates tubuloglomerular feedback (TGF) in type 1 diabetes. Using Zucker lean (ZL) and diabetic fatty (ZDF) rats on normal and high-salt diets, renal hemodynamics and the renin-angiotensin system (RAS) were characterized. On normal salt diet, glomerular filtration rate (GFR) was higher in ZDF than ZL rats. Autoregulation of GFR was less efficient and lithium clearance was lower in ZDF rats than ZL rats. Salt load reduced GFR in ZDF rats with restoration of lithium clearance and partial improvement in autoregulatory index (AI). The administration of 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine-1 receptor antagonist to ZDF rats on a high-salt diet abolished the improvement of AI in GFR. However, this effect was seen by neither (Cx40)GAP27 nor (Cx37,43)GAP27, which inhibits connexin (Cx) 40 or Cx37. Renal ANG II was higher in ZDF than ZL rats on normal salt diet, but the difference was eliminated by a salt load. The present data provide the first demonstration for a salt paradox in type 2 diabetes and implicate that in addition to Cx alterations, an enhanced proximal reabsorption attenuates TGF, underlying glomerular hyperfiltration and RAS activation. These data suggest that a high-salt diet standardizes distal delivery in diabetes, suppressing the RAS, and improving GFR autoregulation and hyperfiltration through adenosine.     

Renal function and glucose transport in male and female mice with diet-induced type II diabetes mellitus

The aim of this study was to measure cardiovascular and renal function, including the renal transport capacity for glucose, in male and female C57BL/6J mice with diet-induced Type II diabetes mellitus. Typical of Type II diabetes, mice fed a high-fat, high-simple carbohydrate diet for 3 months were obese (45-65 g), hyperglycemic (138-259 mg%), and hyperinsulinemic (1.8-15.06 ng/ml); significant gender differences were observed in all cases. Based on systolic pressure measurements in conscious mice and arterial blood pressure measurements in anesthetized mice, no diet-induced hypertension was observed in either male or female mice. Urine flow rate, sodium, potassium, osmolar, and protein excretion rates were significantly increased (P < 0.05) in male mice fed the high-fat, high-simple carbohydrate diet compared with female mice fed the same diet. However, no differences in the excretion variables existed between male and female mice fed the control diet. The glomerular filtration rate (ml min-1 g kw-1), determined by FITC-inulin, in male and female mice fed the control diet (0.87 +/- 0.01 and 0.90 +/- 0.1, respectively) and high-fat, high-simple carbohydrate diet (0.96 +/- 0.1 and 0.93 +/- 0.2, respectively) was not different between the groups. These hyperglycemic mice were also not glucosuric. Infusions of progressive amounts of glucose in male mice fed either diet for 3 or 6 months demonstrated that the renal threshold for glucose was 400 mg% for all these mice, well above the fasting plasma glucose concentrations observed in this study. Thus, C57BL/6J mice were valuable tools for studying diet-induced obesity, hyperglycemia, and hyperinsulinemia; however, no hypertension or kidney dysfunction was apparent within the time frame of the current study.     

Blood pressure in a hypertensive mouse model of SLE is not salt-sensitive

Systemic lupus erythematosus (SLE) is a risk factor for hypertension. Previously, we demonstrated that an established mouse model of SLE (female NZBWF1 mice) develops hypertension with renal inflammation and oxidative stress, both characteristics known as contributing mechanisms to the development of salt-sensitive hypertension. On the basis of this model, we hypothesized that blood pressure in SLE mice would be salt-sensitive. Thirty-week-old female SLE and control mice (NZW/LacJ) were fed 8% high-salt (HS) diet or normal diet (0.4% salt) for 4 wk. Plasma levels of double-stranded DNA (dsDNA) autoantibodies, a marker of SLE disease activity, were increased in SLE mice compared with controls (472 ± 148 vs. 57 ± 17 U/ml × 1,000, P < 0.001). HS did not alter dsDNA autoantibody levels in SLE or control mice. Mean arterial pressure was increased in SLE mice compared with controls (132 ± 3 vs. 118 ± 2 mmHg, P < 0.001) and was not significantly altered by the HS diet in either group. Similarly, albuminuria was higher in SLE mice compared with controls (10.7 ± 9.0 vs. 0.3 ± 0.1 mg/day) but was not significantly increased in SLE or control mice fed a HS diet. In summary, blood pressure during SLE is not salt-sensitive, and the HS diet did not adversely affect SLE disease activity or significantly augment albuminuria. These data suggest that renal inflammation and oxidative stress, characteristics common to both SLE and models of salt-sensitive hypertension, may have diverging mechanistic roles in the development of hypertension.     

Effects of high sodium intake diet on the vascular reactivity to phenylephrine on rat isolated caudal and renal vascular beds: Endothelial modulation

High salt intake is involved in the genesis of hypertension and vascular changes in salt-sensitive patients. Although many mechanisms have been proposed, the underlying mechanisms of these alterations in healthy rats are not completely elucidated. The aim of this study was to investigate if male Wistar rats fed a high salt diet, NaCl 1.8% in drinking water for 4 weeks, develop changes in the pressor reactivity of isolated tail and renal vascular beds. Salt treatment increased mean arterial pressure (SALT = 124 +/- 2.2 vs. CT = 111 +/- 3.9 mmHg; p < 0.01) and urinary sodium excretion in the absence of changes in sodium plasma levels. Pressor reactivity was generated in isolated tail and kidney vascular beds as dose-response curves to phenylephrine (PHE = 0.01 to 300 microg). SALT increased the reactivity (E(max): SALT = 378 +/- 15.8 vs. CT = 282 +/- 10 mmHg; p < 0.01) without changing the sensitivity (pD(2)) to PHE in the tail vascular bed. However, these parameters did not change in the renal bed. In subsequent studies on the isolated caudal vascular bed, we found that endothelial damage, but not L-NAME (100 microM) or indomethacin (10 microM), abolished the increment in E(max) to PHE induced by SALT. On the other hand, losartan (100 microM) reduced E(max) in SALT to CT values. Additionally, local angiotensin-converting enzyme activity in segments from tail artery increased by 95%. In conclusion, 4 weeks of high salt diet increases blood pressure and induces specific territorial vascular changes in response to PHE. Results also suggest that the increment in E(max) in the tail vascular bed from SALT rats was endothelium-dependent and was mediated by the activation of the local renin-angiotensin system.     

Effect of renal medullary H2O2 on salt-induced hypertension and renal injury

Dahl salt-sensitive (SS) and consomic, salt-resistant SS-13(BN) rats possess substantial differences in blood pressure salt-sensitivity even with highly similar genetic backgrounds. The present study examined whether increased oxidative stress, particularly H2O2, in the renal medulla of SS rats contributes to these differences. Blood pressure was measured using femoral arterial catheters in three groups of rats: 1) 12-wk-old SS and consomic SS-13(BN) rats fed a 0.4% NaCl diet, 2) SS rats fed a 4% NaCl diet and chronically infused with saline or catalase (6.9 microg x kg(-1) x min(-1)) directly into the renal medulla, and 3) SS-13(BN) fed high salt (4%) and infused with saline or H2O2 (347 nmol x kg(-1) x min(-1)) into the renal medullary interstitium. After chronic blood pressure measurements, renal medullary interstitial H2O2 concentration ([H2O2]) was collected by microdialysis and analyzed with Amplex red. Blood pressure and [H2O2] were both significantly higher in SS (126 +/- 3 mmHg and 145 +/- 17 nM, respectively) vs. SS-13(BN) rats (116 +/- 2 mmHg and 56 +/- 14 nM) fed a 0.4% diet. Renal interstitial catalase infusion significantly decreased [H2O2] (96 +/- 41 vs. 297 +/- 52 nM) and attenuated the hypertension (146 +/- 2 mmHg catalase vs. 163 +/- 4 mmHg saline) in SS rats after 5 days of high salt (4%). H2O2 infused into the renal medulla of consomic SS-13(BN) fed high salt (4%) for 7 days accentuated the salt sensitivity (145 +/- 2 mmHg H2O2 vs. 134 +/- 1 mmHg saline). [H2O2] was also increased in the treated group (83 +/- 1 nM H2O2 vs. 44 +/- 9 nM saline). These data show that medullary production of H2O2 may contribute to salt-induced hypertension in SS rats and that chromosome 13 of the Brown Norway contains gene(s) that protect against renal medullary oxidant stress.     

Salt intake and depletion increase circulating levels of endogenous ouabain in normal men

High-salt diets elevate circulating Na+ pump inhibitors, vascular resistance, and blood pressure. Ouabain induces a form of hypertension mediated via the alpha2-Na+ pump isoform and the calcium influx mode of the vascular sodium calcium exchanger (NCX). Whereas elevated levels of an endogenous ouabain (EO) and NCX have been implicated in salt-sensitive hypertension, acute changes in sodium balance do not affect plasma EO. This study investigated the impact of longer-term alterations in sodium balance on the circulating levels and renal clearance of EO in normal humans. Thirteen normal men consumed a normal diet, high-salt diet, and hydrochlorothiazide (HCTZ), each for 5-day periods to alter sodium balance. EO and other humoral and urinary variables were determined daily. On a normal diet, urinary sodium excretion (140 +/- 16 meq/day), plasma EO (0.43 +/- 0.08 nmol/l) and urinary EO excretion (1.04 +/- 0.13 nmol/day) were at steady state. On the 3rd day of a high-salt diet, urine sodium excretion (315 +/- 28 meq/day), plasma EO (5.8 +/- 2.2 nmol/l), and the urinary EO excretion (1.69 +/- 0.27 nmol/day) were significantly increased, while plasma renin activity and aldosterone levels were suppressed. The salt-evoked increase in plasma EO was greater in older individuals, in subjects whose baseline circulating EO was higher, and in those with low renal clearance. During HCTZ, body weight decreased and plasma renin activity, aldosterone, and EO (1.71 +/- 0.77 nmol/l) rose, while urinary EO excretion remained within the normal range (1.44 +/- 0.31 nmol/day). Blood pressure fell in one subject during HCTZ. HPLC of the plasma extracts showed one primary peak of EO immunoreactivity with a retention time equivalent to ouabain. High-salt diets and HCTZ raise plasma EO by stimulating EO secretion, and a J-shaped curve relates sodium balance and EO in healthy men. Under normal dietary conditions, approximately 98% of the filtered load of EO is reabsorbed by the kidney, and differences in the circulating levels of EO are strongly influenced by secretion and urinary excretion of EO. The dramatic impact of high-salt diets on plasma EO is consistent with its proposed role as a humoral vasoconstrictor that links salt intake with vascular function in hypertension.     

Fructose-induced hypertension in Wistar-Kyoto rats: interaction with moderately high dietary salt

We investigated the effects of 4% fructose plus moderately high salt (MHS) (4% NaCl) treatment on tissue aldehyde conjugates, platelet cytosolic free calcium ([Ca2+]i), renal morphology, and systolic blood pressure (SBP) in Wistar-Kyoto rats, and whether these effects were reversible (R) after withdrawal of treatment. At age 7 weeks, rats were divided into 4 groups: NS group, given normal salt (NS) diet (0.7% NaCl) for 18 weeks; NS+F(R) group, NS diet and fructose in water for 14 weeks, then 4 weeks fructose withdrawal; MHS+F group, NS diet and fructose for 6 weeks, then MHS diet and fructose for 12 weeks; and MHS+F(R) group, NS diet and fructose for 6 weeks, then MHS diet and fructose for 8 weeks, then MHS and fructose withdrawal for 4 weeks. SBP in the NS+F(R) group increased during fructose treatment, but normalized within 1 week of withdrawal. Tissue aldehyde conjugates and platelet [Ca2+]i were normal at completion. Adverse renal vascular changes did not reverse to normal and were similar to those of the salt plus fructose-treated groups. This may have implications for future development of hypertension. MHS did not cause any additional increase in SBP or associated tissue alterations when added to fructose treatment. However, the SBP and tissue changes persisted even after discontinuation of treatment. The fructose and salt combination may result in long-lasting vascular alterations leading to hypertension.     

Renal and blood pressure phenotype in 18-mo-old bradykinin B2R(-/-)CRD mice

Aberrant gene-environment interactions are implicated in the pathogenesis of congenital renal dysgenesis (CRD), a leading cause of renal failure in infants and children. We have recently developed an animal model of CRD that is caused by gestational salt stress (5% NaCl diet; HS) of bradykinin B2R null mice [B2R(-/-)CRD; El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S. Physiol Genomics 3: 121-131, 2000.]. Developing B2R(-/-)CRD mice exhibit tubular and glomerular cysts, stromal expansion, and loss of corticomedullary differentiation. In addition, B2R(-/-)CRD mice exhibit transient hypertension from 2 to 4 mo of age. The present study was designed to determine the long-term consequences of CRD on renal morphology and salt sensitivity of blood pressure in B2R(-/-)CRD mice. One-year- and 18-mo-old B2R(-/-)CRD mice exhibited stunted renal growth, glomerular cystic abnormalities, and collecting duct ectasia. Moreover, tumors of mesenchymal cell origin emerged in the dysplastic kidneys of 90% of 1-yr-old and 100% of 18-mo-old B2R(-/-)CRD mice but not in age-matched B2R(-/-) or wild-type mice. When challenged with an HS diet, 18-mo-old B2R(-/-)CRD exhibited a significant rise in systolic and diastolic blood pressures and more pronounced natriuresis and diuresis compared with salt-loaded 18-mo-old wild-type mice. Kidney aquaporin-2 expression was decreased by 50%, whereas renin, ANG type 1 receptor, and Na+-K+-ATPase levels were not different in B2R(-/-)CRD mice compared with controls. In conclusion, this study demonstrates that B2R(-/-)CRD mice exhibit permanent phenotypic and functional abnormalities in renal growth and differentiation. This novel model of human disease links gene-environment interactions with renal development and blood pressure homeostasis.     

Kidney function in response to salt feeding in rainbow trout (Salmo gairdneri Richardson)

1. The effect of high levels of dietary salt up to 12% NaCl on kidney function in freshwater rainbow trout was investigated. 2. Renal response to dietary NaCl load includes increases in urinary flow rate and glomerular filtration rate, together with a slight reduction in ionic reabsorption capacity. 3. The renal salt excretion rate, which was doubled to about 100 microM/kg/hr, in fish fed the high salt diet, is not entirely a consequence of a reduction in tubular ionic reabsorption but also of increased glomerular filtration. 4. The role of the endocrine system in control of renal salt excretion is discussed.     

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.     

A high-fat, refined-carbohydrate diet affects renal NO synthase protein expression and salt sensitivity.

Chronic consumption of a high-fat, refined-carbohydrate (HFS) diet causes hypertension. In an earlier study, we found increased nitric oxide (NO) inactivation by reactive oxygen species (ROS) and functional NO deficiency in this model. Given the critical role of NO in renal sodium handling, we hypothesized that diet-induced hypertension may be associated with salt sensitivity. Female Fischer rats were fed an HFS or a standard low-fat, complex-carbohydrate (LFCC) rat chow diet starting at 2 mo of age for 2 yr. Arterial blood pressure, renal neuronal NO synthase (nNOS), endothelial NO synthase (eNOS), and inducible NO synthase (iNOS) protein and nitrotyrosine abundance (a marker of NO inactivation by ROS), and urinary NO metabolite excretion were measured. To assess salt sensitivity, the blood pressure response to a high-salt (4%) diet for 1 wk was determined. After 2 yr, renal nNOS and urinary NO metabolite excretion were significantly depressed, whereas arterial pressure, eNOS, iNOS, and nitrotyrosine were elevated in the HFS group but remained virtually unchanged in the LFCC group. Consumption of the high-salt diet resulted in a significant rise in arterial pressure in the HFS, but not in the LFCC, group. Thus chronic consumption of an HFS diet results in hypertension and salt sensitivity, which may be in part due to a combination of ROS-mediated NO inactivation and depressed renal nNOS protein expression.     

Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats

Excessive salt intake is known to preferentially increase blood pressure (BP) and promote kidney damage in young, salt-sensitive hypertensive human and animal models. We have suggested that mineralocorticoid receptor (MR) activation plays a major role in kidney injury in young rats. BP and urinary protein were compared in young (3-wk-old) and adult (10-wk-old) uninephrectomized (UNx) Sprague-Dawley rats fed a high (8.0%)-salt diet for 4 wk. The effects of the MR blocker eplerenone on BP and renal injury were examined in the high-salt diet-fed young UNx rats. Renal expression of renin-angiotensin-aldosterone (RAA) system components and of inflammatory and oxidative stress markers was also measured. The effects of the angiotensin receptor blocker olmesartan with or without low-dose aldosterone infusion, the aldosterone synthase inhibitor FAD286, and the antioxidant tempol were also studied. Excessive salt intake induced greater hypertension and proteinuria in young rats than in adult rats. The kidneys of young salt-loaded rats showed marked histological injury, overexpression of RAA system components, and an increase in inflammatory and oxidative stress markers. These changes were markedly ameliorated by eplerenone treatment. Olmesartan also ameliorated salt-induced renal injury but failed to do so when combined with low-dose aldosterone infusion. FAD286 and tempol also markedly reduced urinary protein. UNx rats exposed to excessive salt at a young age showed severe hypertension and renal injury, likely primarily due to MR activation and secondarily due to angiotensin receptor activation, which may be mediated by inflammation and oxidative stress.     

Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure

The effects of prenatal protein restriction on adult renal and cardiovascular function have been studied in considerable detail. However, little is known about the effects of life-long protein restriction, a common condition in the developing world. Therefore, we determined in rats the effects of combined pre- and postnatal protein restriction on adult arterial pressure and renal function and responses to increased dietary sodium. Nephron number was also determined. Male Sprague-Dawley rats were born to mothers fed a low [8% (wt/wt), LP] or normal [20% (wt/wt), NP] isocaloric protein diet throughout pregnancy and maintained on these diets after birth. At postnatal day 135, nephron number, mean arterial pressure (MAP), and renal function were determined. A high-NaCl [8.0% (wt/wt), high-salt] diet was fed to a subset of rats from weaning. MAP was less in LP than in NP rats (120 +/- 2 vs. 128 +/- 2 mmHg, P < 0.05) and was not significantly altered by increased salt intake. Nephron number was 31% less in LP than in NP rats (P < 0.001). The volume of individual glomeruli was also less in LP than in NP rats, as were calculated effective renal plasma flow and glomerular filtration rate. Glomerular filtration rate, but not effective renal plasma flow, appeared to be increased by high salt intake, particularly in LP rats. In conclusion, protein restriction induced a severe nephron deficit, but MAP was lower, rather than higher, in protein-restricted than in control rats in adulthood. These findings indicate that the postnatal environment plays a key role in determining the outcomes of developmental programming.     

High nephron endowment protects against salt-induced hypertension

While low nephron number is associated with increased risk of developing cardiovascular and renal disease, the functional consequences of a high nephron number are unknown. We tested the hypothesis that a high nephron number provides protection against hypertensive and renal insults. Mean arterial pressure (MAP) and renal function were characterized in male wild-type (WT) and transforming growth factor-β2 heterozygous (Tgfb2(+/-)) mice under basal conditions and following a chronic high-salt diet. Kidneys were collected for unbiased stereological analysis. Baseline MAP and renal function were indistinguishable between genotypes. The chronic high-salt diet (5% NaCl for 4 wk followed by 8% NaCl for 4 wk) led to similar step-wise increases in urine volume, Na(+) excretion, and albuminuria in the genotypes. The 5% NaCl diet induced modest and similar increases in MAP (3.5 ± 1.6 and 3.4 ± 0.8 mmHg in WT and Tgfb2(+/-), respectively). After the step up to the 8% NaCl diet, MAP increased further in WT (+15.9 ± 5.1 mmHg), but not Tgfb2(+/-) (-0.1 ± 1.0 mmHg), mice. Nephron number was 30% greater in Tgfb2(+/-) than WT mice and was not affected by the chronic high-salt diet. Mean glomerular volume was lower in Tgfb2(+/-) than WT mice, and the chronic high-salt diet induced significant glomerular hypertrophy. In a separate cohort of mice, an acute, 7-day, 8% NaCl diet induced similar rises in MAP in the genotypes. This is the first study to examine the physiological characteristics of a model of high nephron number, and the findings are consistent with this phenotype providing protection against chronic, but not acute, hypertensive insults.