SALT INTAKE AND SENSITIVITY OF INTESTINAL AND RENAL NA<sup>+</sup>-K<sup>+</sup>ATPase TO INHIBITION BY DOPAMINE IN SPONTANEOUS HYPERTENSIVE AND WISTAR-KYOTO RATS

Teixeira, Vera; Vieira-Coelho, Maria Augusta; Serrão, Paula; Pestana, Manuel; Soares-da-Silva, Patrı́cio

doi:10.1081/ceh-100100084

Cited by 25 publications

(20 citation statements)

References 41 publications

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“…33 On the other hand, the mRNA corresponding to LAT2 examined by Northern blot analysis was strongly expressed in the small intestine. 34,35 In agreement with the view that LAT2 might play a role in L-DOPA transport is the recent observation that in opossum kidney (OK) renal tubular cells, L-DOPA uses at least 2 major transporters, systems LAT2 and b 0,ϩ . 17 The transport of L-DOPA by LAT2 corresponds to an Na ϩ -independent transporter with a broad specificity for small and large, neutral amino acids that is stimulated by acid pH and inhibited by 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid.…”

Section: Discussionsupporting

confidence: 48%

Organ-Specific Overexpression of Renal LAT2 and Enhanced Tubular l -DOPA Uptake Precede the Onset of Hypertension

et al. 2003

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Abstract-Spontaneously hypertensive rats (SHR) might have increased renal production of dopamine. L-3,4-Dihydroxyphenylalanine (L-DOPA) uptake in renal epithelial cells is promoted through the type 2 L-type amino acid transporter (LAT2), and this might rate-limit the synthesis of renal dopamine. The present study evaluated L-DOPA uptake in isolated renal proximal tubules of SHR and normotensive controls (Wistar-Kyoto rats [WKY]). Expression of LAT1 and LAT2 in the renal cortex and intestinal mucosa was also evaluated. Tubular uptake of L-DOPA in WKY and SHR was a saturable process, being greater in the latter than the former at both 4 and 12 weeks of age. cDNA fragments (LAT1, 688 bp; LAT2, 729 bp) labeled with 32 P were used as probes for Northern blot analysis. Expression of LAT2 in SHR kidneys was higher than in WKY kidneys. This increase was more marked at 4 than at 12 weeks of age. Intestinal LAT2 expression, however, was identical in SHR and WKY at both 4 and 12 week of age. By Northern blot analysis, the LAT1 transcript was not identified in either the kidney or intestine. Kidney total RNA was then reverse-transcribed and amplified by polymerase chain reaction with specific primers for LAT1. The presence of a fragment of the expected size for LAT1 led to the conclusion that LAT1 mRNA is a rare message in kidney. We conclude that overexpression of LAT2 in the SHR kidney might contribute to the enhanced L-DOPA uptake, which is organ specific and precedes the onset of hypertension.

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Section: Discussionsupporting

confidence: 48%

Organ-Specific Overexpression of Renal LAT2 and Enhanced Tubular l -DOPA Uptake Precede the Onset of Hypertension

et al. 2003

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“…One possible explanation for the increase in urinary Na + and K + in the sik1 −/− mice without evidence of severe sodium depletion, as indicated by normal plasma Na + and K + levels, is that of a possible intestinal absorptive compensatory mechanism to keep electrolyte homeostasis. [32][33][34][35] Although we cannot exclude the possibility that renal function is affected in the sik1 −/− mice during the first days/weeks of HS intake, it is unlikely that the loss of renal SIK1 is responsible for the mild hypertension given that increased urinary Na + excretion, and not the opposite, is observed in these mice. Aldosterone levels did not differ in the sik1 −/− mice, therefore it is plausible to think that in the adrenal glands the other SIK isoforms could display compensatory mechanisms to maintain transducer of regulated cAMP response element-binding phosphorylation levels and indeed in vitro studies in adrenocortical cells showed that SIK2 and SIK3 also phosphorylate this cofactor.…”

Section: Discussionmentioning

confidence: 98%

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

Bertorello

Pires

Igreja

et al. 2015

Circulation Research

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Rationale:In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes.Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1 −/−) and wild-type (sik1 +/+ ) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1 −/− mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1 +/+ mice. During high-salt intake, the sik1 +/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1 −/− mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Bertorello et al SIK1, Hypertension, and Vascular Remodeling 643Elevated arterial blood pressure can occur as a consequence of increased vascular stiffness attributed to both extracellular matrix deposition/remodeling and enhanced contractility/stiffness of VSMCs. [10][11][12][13] Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that mediates extracellular matrix remodeling processes within the vasculature in addition to promote VSMCs differentiation toward a contractile phenotype.14-18 SIK1 participates in a negative feedback mechanism on the TGF-β1 signaling pathway. 19 We have reported that in epithelial cells the loss of SIK1 increased the expression of SNAI2 and TWIST1, known transcription factors involved in fibrosis and extracellular matrix remodeling. Recently, brain SIK1 activity has been shown to be relevant for blood pressure regulation in rodents by regulating sympathetic activity. Higher hypothalamic activity of SIK1 was associated with reduced sympathoexcitatory activity and lower arterial blood pressure in rats after a high-salt diet and intracerebroventricular infusion of Na + . 20Because SIK1 is present in the vasculature and lower SIK1 activity was associated with elevated blood pressure in humans and rodents, we hypothesize that the lack of SIK1 could trigger vascular remodeling processes leading to increased vascular stiffness and consequently to higher blood pressure. Furthermore, these events alone or in combination with other risk factors (high-s...

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“…The sodium balance in our studies was calculated without taking into account fecal sodium excretion. SHR have been reported to have increased intestinal sodium transport, 27,28 although fecal sodium balance was not different between WKY and SHR. 29 The decrease in positive sodium balance in AS-ODN-treated SHR was associated initially with lesser weight gain.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

et al. 2005

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Abstract-The effect of selectively decreasing renal angiotensin II type 1 (AT 1 ) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT 1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT 1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT 1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT 1 receptors. AT 1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT 1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels. Key Words: receptors, angiotensin II Ⅲ rats Ⅲ kidney Ⅲ hypertension, essential Ⅲ proteinuria G enetic manipulations that increase the activity of the renin-angiotensin system (RAS) systemically 1-5 or in specific organs (eg, brain and kidney) elevate blood pressure. 6,7 For example, overexpression of angiotensinogen and renin in renal proximal tubules 6 or in neurons and glia cells in brain 7 increased blood pressure without increasing circulating renin levels. Systemic deletion or silencing of genes that regulate the RAS also decreases blood pressure. Thus, disrupting or silencing angiotensinogen 4 and angiotensinconverting enzyme 1 genes 8,9 or the angiotensin II type 1A receptor (AT 1A R) gene 10,11 in mice or rats decreases blood pressure. Decreasing the expression of liver angiotensinogen also decreases blood pressure in mice. 12 More recently, Crowley et al reported that nephrectomized AT 1A Ϫ/Ϫ mice with 1 transplanted AT 1A ϩ/ϩ kidney had higher blood pressures than those observed in unmanipulated AT 1A Ϫ/Ϫ mice or AT 1A Ϫ/Ϫ mice with a transplanted AT 1A Ϫ/Ϫ kidney but lower than the blood pressures in unmanipulated AT 1A ϩ/ϩ or AT 1A ϩ/ϩ mice with a transplanted AT 1A ϩ/ϩ kidney. 13 These studies showed the importance of renal and extrarenal factors in the regulation of blood pressure. However, there are no reports of the renal functional and blood pressure consequences of silencing the AT 1 R selectively in the kidney of rats with spontaneous hypertension. To test the ...

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SALT INTAKE AND SENSITIVITY OF INTESTINAL AND RENAL NA⁺-K⁺ATPase TO INHIBITION BY DOPAMINE IN SPONTANEOUS HYPERTENSIVE AND WISTAR-KYOTO RATS

Cited by 25 publications

References 41 publications

Organ-Specific Overexpression of Renal LAT2 and Enhanced Tubular l -DOPA Uptake Precede the Onset of Hypertension

Organ-Specific Overexpression of Renal LAT2 and Enhanced Tubular l -DOPA Uptake Precede the Onset of Hypertension

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

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SALT INTAKE AND SENSITIVITY OF INTESTINAL AND RENAL NA+-K+ATPase TO INHIBITION BY DOPAMINE IN SPONTANEOUS HYPERTENSIVE AND WISTAR-KYOTO RATS

Cited by 25 publications

References 41 publications

Organ-Specific Overexpression of Renal LAT2 and Enhanced Tubular l -DOPA Uptake Precede the Onset of Hypertension

Organ-Specific Overexpression of Renal LAT2 and Enhanced Tubular l -DOPA Uptake Precede the Onset of Hypertension

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

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SALT INTAKE AND SENSITIVITY OF INTESTINAL AND RENAL NA⁺-K⁺ATPase TO INHIBITION BY DOPAMINE IN SPONTANEOUS HYPERTENSIVE AND WISTAR-KYOTO RATS