The role of dopamine-metabolizing enzymes in the regulation of renal sodium excretion in the rat

Odlind, Cecilia; Reenilä, Ilkka; Männistö, Pekka T.; Ekblom, Jonas; Hansell, Peter

doi:10.1007/s004240100545

Cited by 13 publications

(21 citation statements)

References 28 publications

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“…Since we in the present study have not tested the dependency of the natriuresis on DA receptors, we cannot categorically state that the blunted natriuretic response in COMT gene deleted mice after acute sodium loading is due to the defective DA system. The wild type mice, however, responded with an increased DA activity after sodium loading, as has previously been demonstrated in rats [11-13,16]. The fact that the homozygous and heterozygous mice did not respond with an increased DA activity after sodium loading strongly indicates a renal dopaminergic defect in these animals.…”

Section: Discussionsupporting

confidence: 60%

Reduced natriuretic response to acute sodium loading in COMT Gene deleted mice

et al. 2002

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Background: The intrarenal natriuretic hormone dopamine (DA) is metabolised by catechol-Omethyltransferase (COMT) and monoamine oxidase (MAO). Inhibition of COMT, as opposed to MAO, results in a potent natriuretic response in the rat. The present study in anaesthetized homozygous and heterozygous COMT gene deleted mice attempted to further elucidate the importance of COMT in renal DA and sodium handling. After acute intravenous isotonic sodium loading, renal function was followed.

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Section: Discussionsupporting

confidence: 60%

Reduced natriuretic response to acute sodium loading in COMT Gene deleted mice

et al. 2002

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“…Once synthesized, dopamine is transported out of the cell to activate tubular dopamine receptors. The amount of dopamine secreted depends, in part, on the activity of two catecholamine-degrading enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) (18,21,27). Indeed, it has been shown that these enzymes are abundant in tubular cells and their inhibition leads to a significant increase in the availability of renal dopamine.…”

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confidence: 99%

Vesicular monoamine transporter 1 mediates dopamine secretion in rat proximal tubular cells

Maurel¹,

Spreux‐Varoquaux²,

Amenta³

et al. 2007

American Journal of Physiology-Renal Physiology

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Renal dopamine, synthesized by proximal tubules, plays an important role in the regulation of renal sodium excretion. Although the renal dopaminergic system has been extensively investigated in both physiological and pathological situations, the mechanisms whereby dopamine is stored and secreted by proximal tubule cells remain obscure. In the present study we investigated whether vesicular monoamine transporters (VMAT)-1 and -2, which participate in amine storing and secretion, are expressed in rat renal proximal tubules, and we defined their involvement in dopamine secretion. By combining RT-PCR, Western blot, and immunocytochemistry we showed that VMAT-1 is the predominant isoform expressed in isolated proximal tubule cells. These results were confirmed by immunohistochemistry analysis of rat renal cortex showing that VMAT-1 was found in proximal tubules but not in glomeruli. Functional studies showed that, as previously reported for VMAT-dependent amine transporters, dopamine release by cultured proximal tubule cells was partially inhibited by disruption of intracellular H(+) gradient. In addition, dopamine secretion was prevented by the VMAT-1/VMAT-2 inhibitor reserpine but not by the VMAT-2 inhibitor tetrabenazine. Finally, we demonstrated that tubular VMAT-1 mRNA and protein expression were significantly upregulated during a high-sodium diet. In conclusion, our results show for the first time the expression of a VMAT in the renal proximal tubule and its involvement in regulation of dopamine secretion. These data represent the first step toward the comprehension of the role of this transporter in renal dopamine handling and its involvement in pathological situations.

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“…Saline loading may also be associated with decreased renal degradation of dopamine by catechol-o-methyl transferase (COMT) (152) to 3-methoxytyramine (3MT) and eventually to homovanillic acid (HVA). Monoamine oxidase A (MAO-A) is more important than MAO-B (but less important than COMT) in the degradation of renal dopamine to dihydroxyphenyl acetic acid (DOPAC) (210) and eventually to HVA; MAO activity is not altered by sodium loading (151). Salt loading also enhances the egress of synthesized dopamine into the tubular lumen rather than into the interstitial space (215 calcium concentrations are low (Ͻ150 nM) (32).…”

Section: Renal Dopamine Receptorsmentioning

confidence: 99%

Functional genomics of the dopaminergic system in hypertension

Zeng

Sanada

Watanabe

et al. 2004

Physiological Genomics

109

172

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Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. Under normal conditions, D 1-like receptors (D1 and D5) inhibit sodium transport in the kidney and intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats (SHRs) and in humans with essential hypertension, the D 1-like receptor-mediated inhibition of epithelial sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is receptor specific, organ selective, nephron-segment specific, precedes the onset of hypertension, and cosegregates with the hypertensive phenotype. The defective transduction of the renal dopaminergic signal is caused by activating variants of G protein-coupled receptor kinase type 4 (GRK4: R65L, A142V, A486V). The GRK4 locus is linked to and GRK4 gene variants are associated with human essential hypertension, especially in saltsensitive hypertensive subjects. Indeed, the presence of three or more GRK4 variants impairs the natriuretic response to dopaminergic stimulation in humans. In genetically hypertensive rats, renal inhibition of GRK4 expression ameliorates the hypertension. In mice, overexpression of GRK4 variants causes hypertension either with or without salt sensitivity according to the variant. GRK4 gene variants, by preventing the natriuretic function of the dopaminergic system and by allowing the antinatriuretic factors (e.g., angiotensin II type 1 receptor) to predominate, may be responsible for salt sensitivity. Subclasses of hypertension may occur because of additional perturbations caused by variants of other genes, the quantitative interaction of which may vary depending upon the genetic background. dopamine; D 1 dopamine receptor; G protein-coupled receptor kinase type 4 THE LONG-TERM REGULATION of blood pressure rests on renal and nonrenal mechanisms (22, 34, 41,82,85,138,143,172). The sympathetic nervous (48,91,133,198,240) and the reninangiotensin (48,62,64,81,82,122,132,143,171,205,221) systems have been shown to be important in the pathogenesis of essential hypertension, including that associated with obesity (43). However, there are several counter-regulatory pathways (39,76,135,142,169,174,184,205,219) (e.g., dopamine pathway), aberrations of which are involved in the pathogenesis of essential hypertension (3, 4, 8-18, 20, 21, 23-26, 29-33, 35, 37, 42, 44-46, 52-60, 67-70, 73-75, 77, 79, 80, 84, 86, 93-95, 97-103, 106-111, 114, 116, 118, 119, 124, 126-128, 130, 131, 136, 140, 141, 144-146, 148-156, 159-161, 163-166, 176-179, 182, 183, 186, 189, 192, 193, 195, 197, 203, 207, 209-216, 218, 224, 226-239), including that associated with obesity (16, 37,201). Dopamine can regulate blood pressure by renal and nonrenal mechanisms (e.g., intestines and central nervous system) (93,130,131,207) that also involve the renin-angiotensin system (12, 29, 46,209,211,212,226,235,236).Because the kidney is important in the long-term regu...

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The role of dopamine-metabolizing enzymes in the regulation of renal sodium excretion in the rat

Cited by 13 publications

References 28 publications

Reduced natriuretic response to acute sodium loading in COMT Gene deleted mice

Reduced natriuretic response to acute sodium loading in COMT Gene deleted mice

Vesicular monoamine transporter 1 mediates dopamine secretion in rat proximal tubular cells

Functional genomics of the dopaminergic system in hypertension

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