Effect of different salt diets on urine output and urinary sodium and potassium excretion in Npr1 mice
As shown in Fig. 6, with a normal salt diet, urine outputs decreased (−) in 1-copy mice (32%, 3.06 ± 0.38, P < 0.05) compared with 2-copy mice (4.49 ± 0.35), but increased (+) in both 3-copy (33%, 5.97 ± 0.47, P < 0.05) and 4-copy (68%, 7.56 ± 0.86, P < 0.05) mice. Similarly, with a low-salt diet, urine outputs decreased (−) in 1-copy mice (28%, 2.38 ± 0.23, P < 0.05) compared with 2-copy mice (3.29 ± 0.19), but increased (+) in 3-copy (36%, 4.48 ± 0.42, P < 0.05) and 4-copy (51%, 4.96 ± 0.44, P < 0.01) mice (Fig. 6a). Also, with a high-salt diet, urine outputs decreased (−) in 1-copy mice (12%, 29.78 ± 0.95, P < 0.01) compared with 2-copy mice (33.79 ± 0.65), but slightly increased (+) in 3-copy (20%, 40.48 ± 1.38, P < 0.001) and 4-copy (27%, 42.97 ± 1.74, P < 0.001) mice (Fig. 6b). Normal salt diet decreased (−) urinary sodium excretions in 1-copy mice (32%, 0.68 ± 0.06, P < 0.001) compared with 2-copy mice (0.99 ± 0.04), but increased (+) in 3-copy (20%, 1.19 ± 0.06, P < 0.05) and 4-copy (35%, 1.33 ± 0.09, P < 0.05) mice (Fig. 7a). At a low-salt diet, urinary sodium excretions decreased (−) in 1-copy mice (27%, 0.024 ± 0.002, P < 0.05) compared with 2-copy mice (0.032 ± 0.003), but increased (+) in 3-copy (48%, 0.048 ± 0.005, P < 0.05) and 4-copy (60%, 0.052 ± 0.006, P < 0.05) mice (Fig. 7b). Also, with a high-salt diet, urinary sodium excretions decreased (−) in 1-copy mice (18%, 12.75 ± 0.48, P < 0.01) compared with 2-copy mice (15.54 ± 0.54), but increased (+) in 3-copy (27%, 19.68 ± 1.18, P < 0.01) and 4-copy mice (31%, 20.35 ± 1.55, P < 0.01, Fig. 7c). There were no statistical differences for urinary potassium excretions in 1-copy, 3-copy and 4-copy mice compared with 2-copy mice with normal salt, low-salt or high-salt diets, respectively (Fig. 8).
Effect of different salt diets on pro-inflammatory cytokines levels in Npr1 mice
Plasma pro-inflammatory cytokines including TNF-α, IL-6 and IL-1α in salt-treated Npr1 mice are shown in Fig. 9a–c. TNF-α levels were increased (+) in low-salt treated 1-copy mice (80%, 18.25 ± 2.12, P < 0.001) compared with 2-copy (10.14 ± 0.92) mice, but decreased (−) in 3-copy (30%, 7.08 ± 0.65, P < 0.05) and 4-copy (43%, 5.78 ± 1.35, P < 0.01) mice. Similarly, with a normal salt diet, TNF-α levels were increased (+) in 1-copy mice (40%, 21.98 ± 2.01, P < 0.01) compared with 2-copy mice (15.66 ± 1.84), but decreased (−) in 3-copy (34%, 10.33 ± 0.71, P < 0.05) and 4-copy (63%, 5.83 ± 0.72, P < 0.05) mice. High-salt diet increased (+) TNF-α levels in 1-copy mice (56%, 30.27 ± 2.32, P < 0.01) but decreased (−) in 3-copy (40%, 11.59 ± 1.51, P < 0.05) and 4-copy (63%, 7.13 ± 0.52, P < 0.05) mice compared with 2-copy mice (19.36 ± 2.49). Likewise, low-salt, normal salt and high-salt diets increased (+) plasma IL-6 levels in 1-copy mice (145%, 34.93 ± 1.73, P < 0.01; 80%, 48.69 ± 1.99, P < 0.01; 95%, 63.07 ± 4.02, P < 0.01, respectively) but decreased (−) in 3-copy (37%, 8.92 ± 1.72, P < 0.05; 36%, 17.22 ± 2.23, P < 0.05; 39%, 19.57 ± 1.94, P < 0.05) and 4-copy (47%, 7.59 ± 1.91, P < 0.05; 62%, 10.32 ± 1.47, P < 0.01; 63%, 11.87 ± 1.71, P < 0.05) mice, respectively, compared with 2-copy controls (14.23 ± 1.77, 27.01 ± 3.02, 32.27 ± 1.50). Plasma IL-1α levels were also increased in low-salt treated 1-copy mice (152%, 14.84 ± 2.31), whereas 3-copy (43%, 3.37 ± 0.43) and 4-copy (62%, 2.26 ± 0.38) mice showed a decrease (−) compared with 2-copy mice. Normal and high-salt diets showed a significant increase (+) in IL-1α levels in 1-copy mice (115%, 20.21 ± 0.72; 70%, 27.83 ± 1.43) but decreased in 3-copy (36%, 6.04 ± 0.63; 44%, 9.10 ± 1.78) and 4-copy (56%, 4.12 ± 0.54; 63%, 6.01 ± 1.08) mice. Cardiac TNF-α, IL-6 and IL-1α levels were significantly increased (+) in 1-copy mice at low-salt (3.5-fold, 9.58 ± 0.78; 37%, 36.55 ± 3.93; two-fold, 50.25 ± 5.14, respectively), normal salt (five-fold, 17.08 ± 1.65; 43%, 56.69 ± 4.62; 2.3-fold, 42.82 ± 4.06, respectively) and high-salt diets (three-fold, 20.86 ± 2.03; 29%, 78.90 ± 9.62; 2.7-fold, 68.12 ± 7.04, respectively) compared with 2-copy mice (Fig. 9d and e). On the contrary, low-salt, normal salt and high-salt diets showed a reduction (−) in cardiac TNF-α levels in 3-copy (37%, 1.71 ± 0.27; 36%, 2.30 ± 0.39; 46%, 3.65 ± 0.26) and 4-copy (52%, 1.30 ± 0.21; 56%, 1.58 ± 0.32; 72%, 1.88 ± 0.35) mice. Further, cardiac IL-6 (36%, 17.06 ± 0.68; 24%, 30.40 ± 3.48; 38%, 37.95 ± 4.97) and IL-1α levels (53%, 10.32 ± 1.21; 44%, 10.40 ± 0.90; 41%, 14.76 ± 1.04) were also decreased (-) in 3-copy (67%, 8.78 ± 1.10; 62%, 15.08 ± 2.07; 52%, 29.36 ± 3.20) and 4-copy (68%, 6.97 ± 0.51; 63%, 6.83 ± 0.91; 63%, 9.28 ± 0.51) mice receiving low-salt, normal salt and high-salt diets (Fig. 9d and e).
Effect of different salt diets on the heart weight to tibia length and heart weight to body weight ratios in Npr1 mice
On a high-salt diet, arterial pressures were increased (+) in 1-copy (11%, P < 0.01) and 2-copy (10%, P < 0.05,) mice, whereas a low-salt diet did not alter arterial pressures in 1-copy, 2-copy, 3-copy or 4-copy mice (Table 1). With a normal salt diet, the heart weight to tibia length ratio increased (+) in 1-copy mice (9.3%, 16.5 ± 0.2, P < 0.05) compared with 2-copy mice (15.1 ± 0.1), but decreased (−) in 4-copy mice (8.6%, 13.8 ± 0.1, P < 0.01) (Table 1). On a low-salt diet, the ratio of heart weight to tibia length decreased (−) in 4-copy mice (10.8%, 13.2 ± 0.4, P < 0.05) compared with 2-copy mice (14.8 ± 0.2). However, on a high-salt diet, this ratio increased (+) in 1-copy mice (10.7%, 17.6 ± 0.6, P < 0.01) compared with 2-copy mice (15.9 ± 0.4), but decreased (−) in 3-copy (11.3%, 14.1 ± 0.3, P < 0.05) and 4-copy (14.5%, 13.6 ± 0.7, P < 0.01) mice. As shown in Table 1, with a normal salt diet, the heart weight to body weight ratio decreased (−) in 4-copy mice (5.0 ± 0.1, P < 0.01) compared with 2-copy mice (5.6 ± 0.2). Similarly on a low-salt diet, the heart weight to body weight ratio also decreased (−) in 4-copy mice (5.1 ± 0.1, P < 0.05) compared with 2-copy mice (5.7 ± 0.1). With a high-salt diet, this ratio decreased (−) in both 3-copy (5.5 ± 0.2, P < 0.01) and 4-copy mice (5.2 ± 0.1, P < 0.001) mice compared with 2-copy mice (6.3 ± 0.1).
Increased cardiac angiotensin II levels in Npr1 mice with a high-salt diet
The present findings provide the evidence that cardiac ANG II levels are increased (+) in Npr1 gene-disrupted mice but decreased (-) in Npr1 gene-duplicated mice in a gene dose-dependent manner. As cardiac ANG II plays roles in cardiac remodelling and function [50,51], an increased cardiac ANG II level may participate in the process of cardiac hypertrophy and heart failure in Npr1 null mutant mice. Previous studies have suggested that most of the cardiac ANG II appears to be produced at tissue sites by the conversion of in-situ synthesized ANG I rather than blood-derived ANG I . Factors such as the circulating renin levels and ANG II binding sites in the heart affect cardiac ANG II production . Enzymatic degradation of ANG II and ANG II-type 1 (AT1) receptor-mediated endocytosis also affect the cardiac ANG II levels . Earlier studies have shown that AT1 receptor signalling in cardiac myocytes and fibroblasts elicits growth and fibrosis . It has been reported that ANP inhibits Ang II-stimulated proliferation in foetal cardiomyocytes, indicating the inhibitory role of ANP-NPRA signalling in cardiac hypertrophy . In comparison with a normal salt diet, a high-salt diet increased (+) cardiac ANG II levels only in 1-copy mice, suggesting that an increased (+) cardiac ANG II may promote cardiac hypertrophy in Npr1 gene-disrupted mice. It has also been reported that a high-salt diet causes cardiac hypertrophy in Dahl salt-sensitive rats .
Cardiac aldosterone levels are elevated in Npr1 mice fed with a high-salt diet
It has been previously reported that a low-salt diet stimulates plasma aldosterone levels, whereas a high-salt diet suppresses its production . In the present study, a low-salt diet increased (+) plasma aldosterone levels in 1-copy, 2-copy, 3-copy and 4-copy mice compared with mice given a normal salt diet. However, a high-salt diet suppressed (−) plasma aldosterone levels in 1-copy mice, but not in 3-copy and 4-copy mice. It is possible that an increased sodium excretion and urine output with a decreased arterial pressure in 3-copy and 4-copy mice attenuate the inhibitory effect of a high-salt diet on plasma aldosterone levels . Our findings suggest that NPRA signalling exerts protective function with regard to blood volume homeostasis and arterial pressure regulation in Npr1 gene-duplicated mice as compared with Npr1 gene-disrupted mice. Interestingly, it has been reported that a high-salt diet did not affect plasma renin activity in ANP gene-knockout mice as compared with wild-type mice . The authors considered that ANP gene-knockout mice develop a salt-sensitive component of hypertension in association with a failure to downregulate plasma renin activity adequately. There were interactions of salt with Npr1 gene copy numbers for both cardiac and plasma aldosterone levels. However, the data on cardiac ALDO synthesis are still controversial [52,53]. The present results suggest that ANP/NPRA/cGMP signalling reduces the cardiac aldosterone levels and protects the heart from cardiac hypertrophy and remodelling process in disease states.
Effect of salt diets on urine volume and urinary sodium, and potassium levels in Npr1 mice
Variations in dietary sodium chloride intake are closely associated with changes in renal renin and Ang II content . Increased sodium excretion and urine output with relatively lower blood pressure in Npr1 gene-duplicated mice may attenuate the inhibitory effect of a high-salt diet on Ang II levels. ANP-NPRA signalling is critical in mediating the natriuresis and diuresis after acute volume expansion [61,62]. In the present study, urinary sodium excretion and urine output decreased (−) in Npr1 1-copy mice as compared with wild-type mice, but increased (+) in Npr1 gene-duplicated (3-copy and 4-copy) mice with a normal salt, a low-salt or a high-salt diet, respectively. Our result indicates that decreased ANP-NPRA signalling can lead to sodium retention that causes blood pressure elevation in Npr1 gene-disrupted mice. On the contrary, increased (+) ANP-NPRA signalling effectively attenuates sodium retention and blood pressure elevation in Npr1 gene-duplicated mice. These present results further support the concept that ANP-NPRA signalling plays a critical role in mediating natriuresis and diuresis in a gene dose-dependent manner.
Elevated levels of cardiac pro-inflammatory cytokines in Npr1 mice fed a high-salt diet
In the present study, the plasma and cardiac cytokine levels were decreased (−) in all the groups receiving a low-salt diet compared with mice receiving a normal salt diet, suggesting that salt restriction could reduce the pro-inflammatory cytokine levels. Similar results have also been reported in rats receiving ANG II for 10 days . The present results showed that TNF-α, IL-6 and IL-1α levels were elevated (+) in both plasma and heart tissues of Npr1 mice on a high-salt diet compared with a normal salt diet. Our previous studies have shown that pro-inflammatory cytokines promote ventricular remodelling and contractile dysfunction in Npr1 mice . Although a high-salt diet showed a significant baseline elevation (+) for all cytokines in 1-copy mice, yet only a small increase occurred in 3-copy and 4-copy mice. The data suggest that increasing Npr1 gene dosage may play a regulatory role in maintaining the pro-inflammatory cytokine levels in sodium-overloaded mice.
Role of a high-salt diet on heart weight/tibia length and heart weight/body weight ratios in Npr1 mice
In the present study, the ratios of heart weight/tibia length and heart weight/body weight increased (+) in Npr1 gene-disrupted 1-copy mice compared with wild-type mice, but decreased (−) in Npr1 gene-duplicated 4-copy mice, implicating that NPRA signalling protects the heart. The high-salt diet increased (+) arterial pressure only in 1-copy and 2-copy mice, but not in 3-copy and 4-copy mice. It has been reported that arterial pressure was decreased (−) in 4-copy mice fed a high-salt diet as compared with 4-copy mice kept on a low-salt diet . Those previous findings suggested that the Npr1 gene, similar to the gene coding for ANP, may directly affect the sensitivity of arterial pressure to salt loading . Although our data provide the evidence that NPRA signalling exerts a protective effect on arterial pressure regulation in mice fed a high-salt diet, in another Npr1 gene-knockout mouse model, a minimal or a high-salt diet did not affect systemic arterial pressure . Both of these models focus on the Npr1 gene disruption, but they have used gene-targeting methods that differ in their details [8,13,62]. However, a similar degree of hypertension has been confirmed in both mouse models. The plasma cGMP levels were decreased (−) in 1-copy mice and increased (+) in 3-copy and 4-copy mice compared with 2-copy mice. The low-salt diet suppressed (−) plasma cGMP levels in all three genotypes of Npr1 mice, whereas the high-salt diet increased (+) plasma cGMP levels in all Npr1 mice. The present results suggest that reduced cGMP signalling increases the heart weight/body weight and heart weight/tibia length ratios impacting cardiac remodelling in Npr1 1-copy gene-disrupted mice.
In conclusion, the present results provide the evidence that cardiac ANG II and aldosterone concentrations are increased (+) in Npr1 gene-disrupted heterozygous (1-copy) mice fed a high-salt diet, however, greatly reduced (−) in Npr1 gene-duplicated (3-copy and 4-copy) mice. The urinary sodium excretion and urine output decreased (−) in Npr1 1-copy mice as compared with wild-type 2-copy mice, but increased (+) in Npr1 gene-duplicated mice. The pro-inflammatory cytokines levels are elevated (+) in both plasma and heart tissues of Npr1 mice kept on a high-salt diet. Furthermore, the high-salt diet showed a significant baseline elevation (+) of pro-inflammatory cytokines in 1-copy and 2-copy mice; yet, the magnitudes of elevation (+) were only small in 3-copy and 4-copy mice. The present results demonstrate that a high-salt diet elevated (+) cardiac ANG II, aldosterone and pro-inflammatory cytokines in 1-copy mice; however, Npr1 gene-duplicated mice did not render such elevated (+) effect indicating the potential role of NPRA against salt-loading and remodelling process in a Npr1 gene dose-dependent manner. The low-salt diet suppressed (−) plasma cGMP levels in all three genotypes of Npr1 mice, whereas the high-salt diet increased (+) plasma cGMP levels in these Npr1 gene-targeted mice. The present results suggest that ANP/NPRA/cGMP signalling decreases (−) the cardiac ANG II, aldosterone and pro-inflammatory cytokine levels and protects the heart from salt-loading and cardiac remodelling process in the disease state.
We thank Ms Gevoni Bolden and Ms Vickie Nguyen for technical assistance and Mrs Kamala Pandey for assistance during the preparation of this manuscript. We gratefully acknowledge the assistance of Dr Sudesh Srivastav, Department of Biostatistics and Bioinformatics, during the statistical analyses of the data. We are indebted to Professor Oliver Smithies for providing us with the initial breeding pairs of Npr1 gene-targeted mice. Our thanks are due to Dr Bharat B. Aggarwal, Department of Experimental Therapeutics and Cytokine Research Laboratory, MD Anderson Cancer Center, and Dr Susan L. Hamilton, Department of Molecular Physiology and Biophysics at Baylor College of Medicine for providing their facilities during our displacement due to Hurricane Katrina.
This study was funded by a grant from the National Institutes of Health (grant no. HL-62147).
Conflicts of interest
The authors have no conflicts of interest.
Reviewer's Summary Evaluations Referee 1
The present study contributes to better clarify the role of NPRA system in the heart. By using a solid experimental approach previously introduced and characterized by the same Authors, i.e. Npr1 gene-knockout and gene-duplication mice, this study provides demonstration that Npr1 blunts the local Ang II and aldosterone levels, and attenuates the generation of pro-inflammatory cytokines in the heart of sodium overloaded-mice.
Investigation of the mechanisms underlying the cardiac protection exerted by Npr1 gene was limited to the plasma and cardiac pro-inflammatory cytokines. Whether other pathways may contribute to the protective effect remains unexplored.
The strength of this study is the choice of the type of animal model used to demonstrate that the natriuretic peptide receptor-A gene (Npr 1) plays a pivotal role in the regulation of the cardiac angiotensin II and aldosterone system as the cardiac angiotensin II and aldosterone concentrations are reduced in a gene dose-related way in the response to a high salt diet in gene duplicated mice which also accounts for a protective effect of the Npr 1 gene against cardiac hypertrophy.
Also, a further important message in this respect is that the increased levels of inflammatory cytokines (TNF-alpha, IL-6, IL-1-alpha) in response to a high salt diet are reduced in gene duplicated mice. However, the observation that the angiotensin II plasma levels were not reduced in gene duplicated mice even though the cardiac angiotensin II concentrations were reduced (which contrasts to the plasma aldosterone levels) still requires further explanation.
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Keywords:© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
aldosterone; angiotensin II; arterial pressure; atrial natriuretic peptide; gene duplication; gene knockout; pro-inflammatory cytokines; salt diet