Natriuretic peptide receptor A mediates renal sodium excretory responses to blood volume expansion

Shi, Shang Jin; Vellaichamy, Elangovan; Chin, So Yeon; Smithies, Oliver; Navar, L. Gabriel; Pandey, Kailash N.

doi:10.1152/ajprenal.00097.2003

Cited by 59 publications

(107 citation statements)

References 45 publications

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“…Assessment of Blood Pressure, Heart Rate, and Cardiac FunctionBlood pressure and heart rate were measured by a noninvasive computerized tail-cuff method using VisiTech 2000 as described previously (23). Blood pressure and heart rate were calculated as the average of six to seven sessions/day for 6 consecutive days.…”

Section: Methodsmentioning

confidence: 99%

Involvement of the NF-κB/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A

Vellaichamy

Khurana

Fink

et al. 2005

Journal of Biological Chemistry

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158

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Mice carrying a targeted disruption of the Npr1 gene (coding for guanylyl cyclase/natriuretic peptide receptor A (NPRA)) exhibit increased blood pressure, cardiac hypertrophy, and congestive heart failure, similar to untreated human hypertensive patients. The objective of this study was to determine whether permanent ablation of NPRA signaling in mice alters the expression of matrix metalloproteinase (MMP)-2 and MMP-9 and proinflammatory mediators such as tumor necrosis factor-␣ (TNF-␣), leading to myocardial collagen remodeling. Here, we report that expression levels of the MMP-2 and MMP-9 genes were increased by 3-5-fold and that the expression of the TNF-␣ gene was enhanced by 8-fold in Npr1 homozygous null mutant (Npr1 ؊/؊ ) mouse hearts compared with wild-type (Npr1 ؉/؉ ) control mouse hearts. Myocardial fibrosis, total collagen, and the collagen type I/III ratio (p < 0.01) were dramatically increased in adult Npr1 ؊/؊ mice compared with agematched wild-type counterparts. Hypertrophic marker genes, including the ␤-myosin heavy chain and transforming growth factor-␤1, were significantly up-regulated (3-5-fold) in both young and adult Npr1 ؊/؊ mouse hearts. NF-B binding activity in ventricular tissues was enhanced by 4-fold with increased translocation of the p65 subunit from the cytoplasmic to nuclear fraction in Npr1 ؊/؊ mice. Our results show that reduced NPRA signaling activates MMP, transforming growth factor-␤1, and TNF-␣ expression in Npr1 ؊/؊ mouse hearts. The findings of this study demonstrate that disruption of NPRA/cGMP signaling promotes hypertrophic growth and extracellular matrix remodeling, leading to the development of cardiac hypertrophy, myocardial fibrosis, and congestive heart failure. Atrial (ANP)1 and brain (BNP) natriuretic peptides elicit natriuretic, diuretic, vasorelaxant, and anti-proliferative responses, all of which contribute to the regulation of blood pressure and blood volume homeostasis (1, 2). ANP and BNP bind to guanylyl cyclase/natriuretic peptide receptor A (NPRA), which is considered a major natriuretic peptide receptor that synthesizes the intracellular second messenger cGMP (3). Mice carrying a targeted disruption of the Npr1 gene (encoding NPRA) exhibit hypertension, marked cardiac hypertrophy, and congestive heart failure, with sudden death after 6 months of age (4 -6). On the other hand, Npr1 gene-duplicated mice have stimulated levels of guanylyl cyclase activity and increased accumulation of intracellular cGMP in a gene dose-dependent manner and exhibit protection against high salt diets (7). In vitro studies have shown that the ANP/NPRA system exerts growth inhibitory effects on hypertrophic agonist-induced proliferation of cardiac myocytes (8, 9), fibroblasts (10), and mesangial and human vascular smooth muscle cells (11,12). Furthermore, transgenic mice overexpressing ANP have smaller hearts compared with wild-type mice, and ANP gene delivery attenuates cardiac hypertrophy in spontaneously hypertensive rats (13). Nonetheless, the molecular mechanism by which the...

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Section: Methodsmentioning

confidence: 99%

Involvement of the NF-κB/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A

Vellaichamy

Khurana

Fink

et al. 2005

Journal of Biological Chemistry

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158

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“…24 RPF was estimated from PAH clearance calculated as the ratio of urine and plasma PAH concentrations times urine flow. GFR was calculated as the ratio of urine and plasma inulin concentrations times urine flow.…”

Section: Urine Plasma Pah and Inulin Measurementsmentioning

confidence: 99%

Acute Angiotensin II Infusions Elicit Pressure Natriuresis in Mice and Reduce Distal Fractional Sodium Reabsorption

Zhao

Navar

2008

Hypertension

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Abstract-Acute angiotensin II (Ang II) infusions into mice increase arterial pressure (AP) and elicit pressure natriuresis.We used this model of pressure natriuresis to delineate the distal nephron responses to AP-mediated increases in distal sodium delivery. In the first group, we measured changes in urinary sodium excretion (U Na V) in male C57/BL6 anesthetized mice (nϭ9) before and during acute Ang II infusions (5 ng/g of body weight per minute). Acute Ang II infusions increased AP (98Ϯ3 to 126Ϯ5 mm Hg; PϽ0.001), urine flow (2.7Ϯ0.5 to 6.0Ϯ0.8 L/min; PϽ0.01), and U Na V (0.6Ϯ0.2 to 1.3Ϯ0.2 Eq/min; PϽ0.05). There were significant relationships between U Na V and urine flow (yϭ0.207xϩ0.030; PϽ0.0001) and between U Na V and AP (yϭ0.027xϪ2.100). In a separate series, distal sodium delivery and fractional reabsorption of distal sodium delivery were determined in control (nϭ12) and Ang II-infused mice (nϭ8) by comparing U Na V before and after blockade of the 2 major distal nephron sodium transporters with amiloride (5 mg/kg of body weight) plus bendroflumethiazide (12 mg/kg of body weight). A positive relationship was found between U Na V (yϭ0.015xϪ1.100; PϽ0.0001) or distal sodium delivery (yϭ0.027xϪ0.900; PϽ0.0001) and AP. An inverse relationship was found between fractional reabsorption of distal sodium delivery and AP (yϭϪ0.511xϩ128.300; PϽ0.01). These data indicate that Ang II-mediated pressure natriuresis involves an increase in distal sodium delivery combined with a reduced distal nephron fractional sodium reabsorption, suggesting that increased AP prevents the distal nephron transport mechanisms from accommodating the increased distal delivery. Key Words: Ang II Ⅲ arterial pressure Ⅲ renal sodium reabsorption Ⅲ distal nephron segments Ⅲ amiloride Ⅲ bendroflumethiazide Ⅲ fractional distal sodium reabsorption I t is well known that increases in arterial pressure (AP) lead to the increases in renal sodium excretion, a phenomenon commonly referred to as pressure natriuresis. [1][2][3][4][5][6][7][8] The changes in renal sodium excretion in response to changes in AP provide a link between the mechanisms regulating sodium excretion and those regulating AP. 1 Because glomerular filtration rate (GFR) and filtered sodium load are autoregulated over the same AP range, the mechanism of pressure natriuresis involves decreased tubular sodium reabsorption in response to increased AP; 6 however, the relative contributions of the various nephron segments responsible have not been fully defined. 5,9 -12 Acute angiotensin II (Ang II) infusions in mice and rats increase AP and elicit pressure natriuresis, suggesting that Ang II infusion is a useful model to delineate the relative contributions of the various nephron segments to increases in AP.The development of a mouse model with minimal surgical interventions to study pressure natriuresis would allow evaluation of the roles of specific tubular transport systems by using various gene targeted models. Although several studies have focused on the AP effects on proximal nephro...

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“…In spite of the hallmark functional significance of NPRA in renal, vascular, and cardiac physiology, the precise mechanisms of receptor activation, regulation, and function at the molecular and genetic levels still remain elusive. Mice carrying the Npr1 gene disruption exhibit hypertension and congestive heart failure (45,60,68). On the other hand, Npr1 gene duplication reduces blood pressure, attenuates hypertrophic stimuli-induced cardiac myocyte growth, and lowers cardiac ANG II and aldosterone levels (46,76,77).…”

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confidence: 99%

Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice

Umadevi

Kumar

Mani

et al. 2016

Physiological Genomics

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Natriuretic peptide receptor A mediates renal sodium excretory responses to blood volume expansion

Cited by 59 publications

References 45 publications

Involvement of the NF-κB/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A

Involvement of the NF-κB/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A

Acute Angiotensin II Infusions Elicit Pressure Natriuresis in Mice and Reduce Distal Fractional Sodium Reabsorption

Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice

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