Renal amino acid transport systems and essential hypertension

Pinto, Vanda; Pinho, Maria João; Soares-da-Silva, Patrı́cio

doi:10.1096/fj.12-224998

Cited by 34 publications

(36 citation statements)

References 103 publications

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“…Dopamine receptors exert beneficial effects by regulating epithelial sodium transport and vascular smooth muscle tone in hypertension [7-12]. Dopamine receptors are classified into D 1 -like and D 2 -like subtypes based on their structure and pharmacology.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Wang

Han

et al. 2014

Cardiovasc Diabetol

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Vascular smooth muscle cells (VSMCs) proliferation and migration, which are central in the development of vascular diseases, are regulated by numerous hormones and humoral factors. Activation of the insulin receptor stimulates VSMCs proliferation while dopamine receptors, via D1 and D3 receptors, inhibit the stimulatory effects of norepinephrine on VSMCs proliferation. We hypothesize that activation of the D4 dopamine receptor may also inhibit the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. Our current study found that insulin increased the proliferation and migration of A10 cells, an effect that was reduced in the presence of a D4 receptor agonist, PD168077. The negative effect of the D4 receptor on insulin’s action may be via decreasing insulin receptor expression, because activation of the D4 receptor inhibited insulin receptor protein and mRNA expressions, indicating that the regulation occured at the transcriptional or post-transcriptional levels. To determine whether or not the inhibition of D4 receptor on insulin-mediated proliferation and migration of VSMCs has physiological significance, hyper-insulinemic Sprague–Dawley rats with balloon-injured carotid artery were treated with a D4 agonist, PD168077, (6 mg/kg/d) for 14 days. We found that PD168077 significantly inhibited neointimal formation by inhibition of VSMC proliferation. This study suggests that activation of the D4 receptor suppresses the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. The D4 receptor may be a potential therapeutic target to reduce the effects of insulin on artery remodeling.

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Section: Introductionmentioning

confidence: 99%

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Wang

Han

et al. 2014

Cardiovasc Diabetol

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“…Proximal tubule cells are the main source of renal DA in mammalian kidney, which majorly result from L-dopa that is freely filtered in the glomerulus, reabsorbed and converted to DA [30, 31, 32]. L-dopa uptake in renal epithelial cells is promoted through the sodium independent and pH-sensitive L-type amino acids transporter type 2 (LAT2), being its activity a rate-limit point for the synthesis of renal dopamine [32, 33].…”

Section: Discussionmentioning

confidence: 99%

L-Tyr-Induced Phosphorylation of Tyrosine Hydroxylase at Ser40: An Alternative Route for Dopamine Synthesis and Modulation of Na+/K+-ATPase in Kidney Cells

Taveira-da-Silva

Sampaio

Vieyra

et al. 2019

Kidney Blood Press Res

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Background/Aims: Dopamine (DA) is a natriuretic hormone that inhibits renal sodium reabsorption, being Angiotensin II (Ang II) its powerful counterpart. These two systems work together to maintain sodium homeostasis and consequently, the blood pressure (BP) within normal limits. We hypothesized that L-tyrosine (L-tyr) or L-dihydroxyphenylalanine (L-dopa) could inhibit the Na⁺/K⁺-ATPase activity. We also evaluated whether L-tyr treatment modulates Tyrosine Hydroxylase (TH). Methods: Experiments involved cultured LLCPK₁ cells treated with L-tyr or L-dopa for 30 minutes a 37°C. In experiments on the effect of Dopa Descarboxylase (DDC) inhibition, cells were pre incubated for 15 minutes with 3-Hydroxybenzylhydrazine dihydrochloride (HBH), and them L-dopa was added for 30 minutes. Na⁺/K⁺-ATPase activity was quantified colorimetrically. We used immunoblotting and immunocytochemistry to identify the enzymes TH, DDC and the dopamine receptor D₁R in LLCPK₁ cells. TH activity was accessed by immunoblotting (increase in the phosphorylation). TH and DDC activities were also evaluated by the modulation of the Na⁺/K⁺-ATPase activity, which can be ascribed to the synthesis of dopamine. Results: LLCPK₁ cells express the required machinery for DA synthesis: the enzymes TH, and (DDC) as well as its receptor D₁R, were detected in control steady state cells. Cells treated with L-tyr or L-dopa showed an inhibition of the basolateral Na⁺/K⁺-ATPase activity. We can assume that DA formed in the cytoplasm from L-tyr or L-dopa led to inhibition of the Na⁺/K⁺-ATPase activity compared to control. L-tyr treatment increases TH phosphorylation at Ser⁴⁰ by 100%. HBH, a specific DDC inhibitor; BCH, a LAT2 inhibitor; and Sch 23397, a specific D₁R antagonist, totally suppressed the inhibition of Na⁺/K⁺-ATPase activity due to L-dopa or L-tyr administration, as indicated in the figures. Conclusion: The results indicate that DA formed mainly from luminal L-tyr or L-dopa uptake by LAT2, can inhibit the Na⁺/K⁺-ATPase. In addition, our results showed for the very first time that TH activity is also significantly increased when the cells were exposed to L-tyr.

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“…L-DOPA is filtered by the glomerulus and reabsorbed by the renal proximal tubule via at least two sodium-independent amino acid transporters, L-type amino acid transporter type 2 (LAT-2) and rBAT/b0,+; LAT-1 may also participate, especially in the spontaneously hypertensive rat (45, 46). B0,+ is present mainly in the apical membrane while LAT-1 and LAT-2 are present mainly at the basolateral membranes of renal proximal tubules (46). Two sodium-dependent amino acid transporters (ASCT2 and B0AT1), expressed at the renal proximal tubular luminal membrane, may also be involved in the renal proximal tubular transport of L-DOPA (46).…”

Section: Gastrin As the Effector Of Gut Sodium Sensormentioning

confidence: 99%