Over-expression of renal LAT1 and LAT2 and enhanced L-DOPA uptake in SHR immortalized renal proximal tubular cells

Pinho, Maria João; Serrão, Paula; Gomes, Pedro; Hopfer, Ulrich; José, Pedro A.; Soares-da-Silva, Patrı́cio

doi:10.1111/j.1523-1755.2004.00722.x

Cited by 47 publications

(45 citation statements)

References 34 publications

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“…Recently, we reported that overexpression of type 2 Na ϩ -independent L-type amino acid transporter (LAT2) in the SHR kidney may contribute to the enhanced L-DOPA uptake (41). In line with these findings, immortalized renal proximal tubular epithelial cells from the SHR also overexpressed LAT2 (42). However, only 25% of L-DOPA uptake in SHR cells occurred through LAT2; 50% of L-DOPA occurred through LAT1 and the remaining 25% through Na ϩ -dependent transport systems.…”

supporting

confidence: 71%

“…Discrepancies between the present study and the findings previously reported (42), namely on the expression of LAT2 in 12-wk-old SHR relative to WKY observed in the latter, may be related to the use of different experimental methods (Northern blot vs. quantitative RT-PCR) to detect LAT2 mRNA. However, it should be underlined that the results on differences in the abundance of LAT2 transcript in 4-wk-old SHR and WKY reported here using quantitative RT-PCR and those in a previous study (42) using Northern blot techniques were identical.…”

Section: Discussionmentioning

confidence: 70%

“…Altogether, these results suggest that the HS intake-induced increase in urinary dopamine may result from the contribution of Na ϩ -dependent transport systems for L-DOPA uptake, especially in the SHR. Previous studies already identified that a minor component of L-DOPA uptake (25%) in SHR immortalized RPT cells was found to require extracellular Na ϩ (42). Discrepancies between the present study and the findings previously reported (42), namely on the expression of LAT2 in 12-wk-old SHR relative to WKY observed in the latter, may be related to the use of different experimental methods (Northern blot vs. quantitative RT-PCR) to detect LAT2 mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Differences in L-DOPA handling between SHR and WKY may result from the overexpression of Na ϩ -independent LAT1 and LAT2 transporters and the contribution of a Na ϩ -dependent amino acid transporter in the former (42), but it is unknown how salt loading affects the expression of these transporters in SHR and WKY. The hypothesis we would like to explore is whether the increased dopamine production and excretion in the SHR, observed during salt loading, are accompanied by overexpression of renal Na ϩ -independent amino acid transporters such as LAT1 and LAT2 or also affect the expression of Na ϩ -dependent amino acid transport systems.…”

mentioning

confidence: 99%

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High-salt intake and the renal expression of amino acid transporters in spontaneously hypertensive rats

Pinho

Serrão²,

Soares-da-Silva³

2007

American Journal of Physiology-Renal Physiology

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Pinho MJ, Serrão MP, Soares-da-Silva P. High-salt intake and the renal expression of amino acid transporters in spontaneously hypertensive rats. Am J Physiol Renal Physiol 292: F1452-F1463, 2007. First published January 30, 2007 doi:10.1152/ajprenal.00465.2006.-This study evaluated in spontaneously hypertensive rats (SHR) and WistarKyoto rats (WKY) the response to salt loading of the renal dopaminergic system and transcript abundance of Na ϩ -independent (LAT1 and LAT2) and Na ϩ -dependent (ASCT2 and B 0 AT1) amino acid transporters potentially involved in renal tubular uptake of L-DOPA. Rats were fed normal (NS)-or high (HS; 1% saline as drinking water)-salt intake for 24 h. Transcript abundance of amino acid transporters was age dependent, differently regulated in WKY and SHR and responded differently to salt intake. HS intake similarly increased urinary dopamine in 4-wk-old SHR and WKY. At 12 wk of age, HS intake increased urinary dopamine in SHR, but not in WKY. Changes in urinary dopamine paralleled changes in the uptake of L-DOPA in isolated renal tubules from 4-and 12-wk-old WKY and SHR on NS and HS intake. At 12 wk of age, HS intake was accompanied by decreases in LAT1 and LAT2 transcript abundance in WKY and SHR. ASCT2 and B 0 AT1 expression was significantly decreased in both 4-and 12-wk-old WKY and in 4-wk-old SHR on HS intake. By contrast, HS intake increased ASCT2 and B 0 AT1 expression in 12-wk-old SHR. It is concluded that salt-sensitive mechanisms influence LAT1, LAT2, ASCT2, and B 0 AT1 gene transcription. Differences in urinary dopamine and tubular uptake of L-DOPA between WKY and SHR during HS intake, namely in 12-wk-old animals, may result from increases in the ASCT2 and B 0 AT1 mRNA levels and less pronounced decreases in LAT2 expression.LAT2; ASCT2; B 0 AT1; kidney; hypertension THE OCCURRENCE OF HYPERTENSION in humans and laboratory animals is associated with the disruption of normal sodium excretion (7). During moderate salt intake, renal dopamine as a result of D 1 -like receptor activation is responsible for ϳ50% of the sodium excretion (19,37,50). Sodium transport is modulated by renal dopamine, which has its origin in renal proximal tubule (RPT) cells and has been shown to act as an autocrine/paracrine substance (50). Dopamine-induced natriuresis that results from the activation of dopamine D 1 -like receptors is associated with decreases in the activities of the Na ϩ -K ϩ -ATPase and the Na ϩ -H ϩ exchanger (10,15,29,35,63). On the other hand, sodium has been found to constitute an important stimulus for the production of dopamine by RPT cells (53,54,56), resulting in increases in the urinary excretion of dopamine and dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) (3,14,18,60,61).The spontaneously hypertensive rat (SHR) is the most used experimental model for naturally occurring hypertension, in which salt loading amplifies the structural and functional cardiac and renal changes associated with long-standing hypertension (12). In the SHR, dopa...

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supporting

confidence: 71%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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High-salt intake and the renal expression of amino acid transporters in spontaneously hypertensive rats

Pinho

Serrão²,

Soares-da-Silva³

2007

American Journal of Physiology-Renal Physiology

Self Cite

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“…3). The inhibitory effect of dopamine on Na ϩ -K ϩ -ATPase is influenced by intracellular sodium and calcium; dopamine inhibits Na (86,164,165). L-DOPA is the sole source of renal tubular dopamine production.…”

Section: Renal Dopamine Receptorsmentioning

confidence: 99%

Functional genomics of the dopaminergic system in hypertension

Zeng

Sanada

Watanabe

et al. 2004

Physiological Genomics

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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 Transporters in Drug Delivery and Excretion

Morris

Guan

2016

Drug Delivery

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Over-expression of renal LAT1 and LAT2 and enhanced L-DOPA uptake in SHR immortalized renal proximal tubular cells

Abstract: Differences in L-DOPA handling between SHR and WKY cells may result from over-expression of LAT1 and LAT2 transporters in the former. The unique role of Na(+)-dependent transporters (system B(0)) in SHR cells also contributes to the enhanced L-DOPA uptake in these cells.

Cited by 47 publications

References 34 publications

High-salt intake and the renal expression of amino acid transporters in spontaneously hypertensive rats

High-salt intake and the renal expression of amino acid transporters in spontaneously hypertensive rats

Functional genomics of the dopaminergic system in hypertension

The Role of Transporters in Drug Delivery and Excretion

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