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      Angiotensin II Regulates Extraneuronal Dopamine Uptake in the Kidney

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          Background/Aims: Angiotensin II (ANG II) and dopamine (DA) are both important regulators of sodium and water transport across renal proximal tubules. Previous studies demonstrate that atrial natriuretic factor (ANF) can regulate renal DA uptake and thereby Na<sup>+</sup>,K<sup>+</sup>-ATPase activity in the external renal cortex. As ANG II counteracts most of the ANF biological effects, the aim of the present study was to evaluate ANG II effects on renal DA metabolism and identify the receptor involved. Methods: To determine ANG II effects on renal DA metabolism, we evaluated <sup>3</sup>H-DA uptake in vitro in kidney tissue samples from Sprague-Dawley rats. Results: The results indicate that ANG II decreased DA uptake at 30 min, in a concentration-response fashion, in the external and juxtamedullar cortex. DA uptake was characterized as an extraneuronal uptake and decreased at 0°C and in sodium-free medium. The biological receptor type involved was AT<sub>1</sub>, since losartan reversed ANG II effects on DA uptake while AT<sub>2</sub> receptors were not involved since PD 123319 did not affect ANG II effects. The absence of sodium did not alter the ANG II response. Conclusion: ANG II inhibits DA uptake by kidney tubular cells. These effects implicate AT<sub>1</sub> receptors without participation of AT<sub>2</sub> receptors. This mechanism could be related to the DA effects on sodium reabsorption and linked to ANG II antinatriuretic effects in the kidney.

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          Most cited references 22

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          The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease.

          The renin-angiotensin-aldosterone system regulates renal vasomotor activity, maintains optimal salt and water homeostasis, and controls tissue growth in the kidney. However, pathologic consequences can result from overactivity of this cascade, involving it in the pathophysiology of kidney disease. An activated renin-angiotensin-aldosterone system promotes both systemic and glomerular capillary hypertension, which can induce hemodynamic injury to the vascular endothelium and glomerulus. In addition, direct profibrotic and proinflammatory actions of angiotensin II and aldosterone may also promote kidney damage. The majority of the untoward effects associated with angiotensin II appear to be mediated through its binding to the angiotensin II type 1 receptor. Aldosterone can also induce renal injury by binding to its receptor in the kidney. An understanding of this system is important to appreciate that inhibitors of this cascade can reduce the progression of chronic kidney disease in proteinuric disease states. Pharmacologic agents that can interfere with this cascade include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists. This paper will provide an overview of the renin-angiotensin system, review its role in kidney disease, examine the renal effects of inhibition of this cascade in experimental animal models, and review clinical studies utilizing renin-angiotensin-aldosterone inhibitors in patients with diabetic and nondiabetic nephropathies.
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            The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines.

            Catecholamines are translocated across plasma membranes by transporters that belong to two large families with mainly neuronal or extraneuronal locations. In mammals, neuronal uptake of catecholamines involves the dopamine transporter (DAT) at dopaminergic neurons and the norepinephrine transporter (NET) at noradrenergic neurons. Extraneuronal uptake of catecholamines is mediated by organic cation transporters (OCTs), including the classic corticosterone-sensitive extraneuronal monoamine transporter. Catecholamine transporters function as part of uptake and metabolizing systems primarily responsible for inactivation of transmitter released by neurons. Additionally, the neuronal catecholamine transporters, recycle catecholamines for rerelease, thereby reducing requirements for transmitter synthesis. In a broader sense, catecholamine transporters function as part of integrated systems where catecholamine synthesis, release, uptake, and metabolism are regulated in a coordinated fashion in response to the demands placed on the system. Location is also important to function. Neuronal transporters are essential for rapid termination of the signal in neuronal-effector organ transmission, whereas non-neuronal transporters are more important for limiting the spread of the signal and for clearance of catecholamines from the bloodstream. Besides their presynaptic locations, NET and DAT are also present at several extraneuronal locations, including syncytiotrophoblasts of the placenta and endothelial cells of the lung (NET), stomach and pancreas (DAT). The extraneuronal monoamine transporter shows a broad tissue distribution, whereas the other two non-neuronal catecholamine transporters (OCT1 and OCT2) are mainly localized to the liver, kidney, and intestine. Altered function of peripheral catecholamine transporters may be involved in disturbances of the autonomic nervous system, such as occurs in congestive heart failure and hypernoradrenergic hypertension. Peripheral catecholamine transporters provide important targets for clinical imaging of sympathetic nerves and diagnostic localization and treatment of neuroendocrine tumors, such as neuroblastomas and pheochromocytomas.
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              Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain.

              We investigated the transport of cationic neurotoxins and neurotransmitters by the potential-sensitive organic transporter OCT3 and its steroid sensitivity using heterologous expression systems and also analyzed the expression of OCT3 in the brain. When expressed in mammalian cells, OCT3 mediates the uptake of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and the neurotransmitter dopamine. Competition experiments show that several cationic neuroactive agents including amphetamines interact with OCT3. When expressed in Xenopus laevis oocytes, OCT3-mediated MPP+ uptake is associated with inward currents under voltage-clamp conditions. The MPP+-induced currents are saturable with respect to MPP+ concentration, and half-maximal saturation (K0.5) occurs at about 25 microM MPP+ with membrane potential clamped at -50 mV. The K0.5 for MPP+ is markedly influenced by membrane potential. OCT3 is inhibited by several steroids, and beta-estradiol is the most potent inhibitor (Ki approximately 1 microM). The pattern of steroid sensitivity of OCT3 is different from that of OCT1 and OCT2 but correlates significantly with that of the extraneuronal monoamine transporter (uptake2). The transport characteristics and steroid sensitivity provide strong evidence for the molecular identity of OCT3 as uptake2. OCT3 is expressed in the brain as evidenced from Northern blot analysis, reverse transcription-polymerase chain reaction, and in situ hybridization using OCT3-specific probes. The molecular identity of the transcript hybridizing to the probe has been established by sequencing the reverse transcription-polymerase chain reaction product and also by the isolation of the OCT3 cDNA from a brain cDNA library. Regional distribution studies with in situ hybridization show that OCT3 is expressed widely in different brain regions, especially in the hippocampus, cerebellum, and cerebral cortex. OCT3 is likely to play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                November 2006
                01 December 2006
                : 104
                : 4
                : p136-p143
                Cátedra de Fisiopatología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
                95856 Nephron Physiol 2006;104:p136–p143
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 40, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/95856
                Original Paper

                Cardiovascular Medicine, Nephrology

                Kidney, Angiotensin II, AT1 receptor, AT2 receptor, Dopamine


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