Receptors for atrial natriuretic peptide are decreased in the kidney of rats with streptozotocin-induced diabetes mellitus.

Sechi, Leonardo A.; Valentin, Jean‐Pierre; Griffin, Chandi; Lee, E; Bartoli, Ettore; Humphreys, Michael H.; Schambelan, Morris

doi:10.1172/jci117945

Cited by 40 publications

(26 citation statements)

References 49 publications

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“…In streptozotocin-induced diabetes, these acute effects of BNP were preserved, unlike those of bradykinin or ACE or neutral endopeptidase inhibition. The cyclic GMP-response to BNP was blunted in diabetic hearts, suggesting a potential downregulation of cardiac NP A receptors, as has been reported in the diabetic kidney (25). However, the BNP-induced rise in cyclic GMP was clearly sufficient to counter the response to angiotensin II.…”

Section: Discussionsupporting

confidence: 57%

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

et al. 2003

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Stimulation of cardiomyocyte guanosine 3,5-cyclic monophosphate (cyclic GMP) via endothelial-derived nitric oxide (NO) is an important mechanism by which bradykinin and ACE inhibitors prevent hypertrophy. Endothelial NO dysfunction and cardiac hypertrophy are morbid features of diabetes not entirely prevented by ACE inhibitors. In cardiomyocyte/endothelial cell cocultures, bradykinin efficacy is abolished by highglucose-induced endothelial NO dysfunction. We now demonstrate that antihypertrophic actions of natriuretic peptides, which stimulate cyclic GMP independently of NO, are preserved in cardiomyocytes despite high-glucose-induced endothelial dysfunction. Further, streptozotocin-induced diabetes significantly impairs the effectiveness of acute antihypertrophic strategies in isolated rat hearts. In hearts from citrate-treated control rats, angiotensin II-stimulated [ 3 H]phenylalanine incorporation and atrial natriuretic peptide and ␤-myosin heavy chain mRNA expression were prevented by B-type natriuretic peptide (BNP), bradykinin, the ACE inhibitor ramiprilat, and the neutral endopeptidase inhibitor candoxatrilat. These antihypertrophic effects were accompanied by increased left ventricular cyclic GMP. In age-matched diabetic hearts, the antihypertrophic and cyclic GMP stimulatory actions of bradykinin, ramiprilat, and candoxatrilat were absent. However, the blunting of hypertrophic markers and accompanying increases in cyclic GMP stimulated by BNP were preserved in diabetes. Thus BNP, which increases cyclic GMP independently of NO, is an important approach to prevent growth in the diabetic myocardium, where endothelium-dependent mechanisms are compromised.

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Section: Discussionsupporting

confidence: 57%

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

et al. 2003

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“…This may be important physiologically because studies have shown that increased osmolarity resulting from uncontrolled diabetes is an important factor in causing the vascular complications associated with this disease. In fact, NPR-A is desensitized in animal models (19) as well as in human subjects (20) with uncontrolled insulin-dependent diabetes. It is therefore quite possible that a mechanism similar to the one we described for NPR-B may explain this process.…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent Dephosphorylation Mediates the Hyperosmotic and Lysophosphatidic Acid-dependent Inhibition of Natriuretic Peptide Receptor-B/Guanylyl Cyclase-B

Potthast

Abbey-Hosch

Antos

et al. 2004

Journal of Biological Chemistry

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C-type natriuretic peptide binding to natriuretic peptide receptor-B (NPR-B) stimulates cGMP synthesis, which regulates vasorelaxation, cell proliferation, and bone growth. Here, we investigated the mechanistic basis for hyperosmotic and lysophosphatidic acid-dependent inhibition of NPR-B. Whole cell cGMP measurements and guanylyl cyclase assays indicated that acute hyperosmolarity decreased NPR-B activity in a reversible, concentration-and time-dependent manner, whereas chronic exposure had no effect. Acute hyperosmolarityelevatedintracellularcalciuminaconcentrationdependent fashion that paralleled NPR-B desensitization. A calcium chelator, but not a protein kinase C inhibitor, blocked both calcium elevations and desensitization. Hyperosmotic medium stimulated NPR-B dephosphorylation, and the receptor was rapidly rephosphorylated and resensitized when the hypertonic media was removed. Lysophosphatidic acid also inhibited NPR-B in a calcium-and phosphorylation-dependent process, consistent with calcium being a universal regulator of NPR-B. The absolute requirement of dephosphorylation in this process was demonstrated by showing that a receptor with glutamates substituted at all known NPR-B phosphorylation sites is unresponsive to hyperosmotic stimuli. This is the first study to measure the phosphorylation state of an endogenous guanylyl cyclase and to link intracellular calcium elevations with its dephosphorylation.The mammalian natriuretic peptide family consists of three members: atrial natriuretic peptide (ANP), 1 brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) (1). ANP and BNP are produced in atrial and ventricular myocytes, respectively. ANP reduces blood pressure by stimulating sodium and water excretion, by stimulating vasorelaxation, and by inhibiting renin and aldosterone secretion. CNP is most highly expressed in the brain (2), endothelial cells (3), and chondrocytes (4, 5). It relaxes vascular smooth muscle cells (6) and inhibits their proliferation (7), a process that has been exploited to inhibit vascular restenosis and to stimulate vascular regeneration (8). In addition, CNP stimulates the proliferation of chondrocytes, which promotes the growth of long bones (4, 5). Natriuretic peptide receptors are structurally related cell surface guanylyl cyclases called natriuretic peptide receptor-A (NPR-A) and natriuretic peptide receptor-B (NPR-B) or guanylyl cyclase-A and guanylyl cyclase-B (9 -11). They consist of an extracellular ligand binding domain, a single membrane-spanning region and intracellular kinase homology, dimerization, and carboxyl-terminal guanylyl cyclase domains. ANP and BNP activate NPR-A, whereas CNP activates NPR-B. Binding of these receptors by their respective ligands stimulates the synthesis of the intracellular second messenger, cGMP.The mechanisms regulating NPR-A and NPR-B activity are incompletely understood. It is known, however, that receptor phosphorylation is required for natriuretic peptide activation and that prolonged exposure to natriuretic peptid...

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“…Because the role of this fundamental mechanism in the regulation of NPR-A and NPR-B remains ambiguous and because receptor down-regulation has been implicated in the desensitization of natriuretic peptide receptors that accompanies various pathologies, such as congestive heart failure (Tsutamoto et al, 1993;Kim et al, 1999) and diabetes (Sechi et al, 1995), we initiated experiments designed to resolve these important issues. For the first time, we measured both the desensitization and internalization of NPR-A and NPR-B in the same cell system.…”

mentioning

confidence: 99%

Down-Regulation Does Not Mediate Natriuretic Peptide-Dependent Desensitization of Natriuretic Peptide Receptor (NPR)-A or NPR-B: Guanylyl Cyclase-Linked Natriuretic Peptide Receptors Do Not Internalize

et al. 2004

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Natriuretic peptide receptor A (NPR-A/GC-A) and B (NPR-B/ GC-B) are members of the transmembrane guanylyl cyclase family that mediate the effects of natriuretic peptides via the second messenger, cGMP. Despite numerous reports of these receptors being down-regulated in response to various pathological conditions, no studies have actually measured desensitization and receptor internalization in the same cell line. Furthermore, the ligand-dependent trafficking properties of NPR-A remain controversial, whereas nothing is known about the trafficking of NPR-B. In this report, we tested whether downregulation explains the ligand-dependent desensitization of NPR-A and NPR-B and characterized their trafficking properties using a combination of hormone-binding and antibodybased assays. Quantitative partition analysis indicated that 125 I-atrial natriuretic peptide (ANP) was rapidly released into the medium after 293T cells stably expressing NPR-A were warmed from 4°to 37°C. High-performance liquid chromatography fractionation of medium supplemented with the protease inhibitor phosphoramidon indicated that the 125 I-ANP was mostly intact. In contrast, 125 I-ANP purified from medium bathing cells expressing NPR-C, a receptor known to internalize natriuretic peptides, was degraded. Cleavable biotinylation and noncleavable biotinylation assays indicated that neither NPR-A nor NPR-B was internalized or degraded in response to natriuretic peptide binding. In contrast, agonist-dependent internalization of a G protein-coupled receptor was clearly apparent in the same cell line. Finally, we show that NPR-A and NPR-B are desensitized in cells in which they are not internalized. We suggest that mechanisms other than receptor down-regulation account for the desensitization of NPR-A and NPR-B that occurs in response to various physiological and pathological stimuli.Atrial natriuretic peptide (ANP), brain natriuretic peptide, and C-type natriuretic peptide (CNP) comprise the mammalian natriuretic peptide family (Levin et al., 1998). ANP and brain natriuretic peptide are endocrine cardiac hormones that decrease blood pressure through the stimulation of renal sodium and water excretion, vasorelaxation, and antagonization of the renin-angiotensin-aldosterone system. CNP signals in a paracrine fashion to stimulate vasorelaxation and long bone growth. The known effects of natriuretic peptides are mediated through the two cell-surface guanylyl cyclase receptors (Schulz and Waldman, 1999;Potter and Hunter, 2001;Silberbach and Roberts, 2001;Misono, 2002;Tremblay et al., 2002). NPR-A, also known as GC-A, is selectively activated by ANP and brain natriuretic peptide, whereas NPR-B, also known as GC-B, is activated by CNP. Both receptors consist of an extracellular ligand-binding domain, a single membrane-spanning region, and intracellular kinase homology, dimerization, and carboxyl-terminal guanylyl cyclase domains. In addition, all three natriuretic peptides bind a third protein called the natriuretic peptide clearance receptor (NPR-C)...

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Receptors for atrial natriuretic peptide are decreased in the kidney of rats with streptozotocin-induced diabetes mellitus.

Cited by 40 publications

References 49 publications

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

Calcium-dependent Dephosphorylation Mediates the Hyperosmotic and Lysophosphatidic Acid-dependent Inhibition of Natriuretic Peptide Receptor-B/Guanylyl Cyclase-B

Down-Regulation Does Not Mediate Natriuretic Peptide-Dependent Desensitization of Natriuretic Peptide Receptor (NPR)-A or NPR-B: Guanylyl Cyclase-Linked Natriuretic Peptide Receptors Do Not Internalize

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