Regulation of Angiotensin II Receptor Subtypes by Dexamethasone in Rat Mesangial Cells

Chansel, Dominique; Llorens-Cortes, Catherine; Vandermeersch, Sophie; Pham, Paul; Ardaillou, Raymond

doi:10.1161/01.hyp.27.4.867

Cited by 28 publications

(20 citation statements)

References 32 publications

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“…Most studies that have investigated the effect of glucocorticoids on AT1R regulation in rodents do not distinguish between the receptor subtypes (19). However, Chansel et al (4) reported that rat mesangial cells cultured in the presence of DEX have a reduced expression of AT1Rb with no alteration in the expression of AT1Ra, whereas Uno et al (27) reported increased expression of AT1Ra with no change in expression of AT1Rb in smooth muscle cells cultured in DEX. These conflicting results may reflect relative expression levels of the receptor subtypes in specific cell populations.…”

Section: Discussionmentioning

confidence: 99%

Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies

Singh¹,

Moritz²,

Bertram³

et al. 2007

American Journal of Physiology-Renal Physiology

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Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies. Am J Physiol Renal Physiol 293: F548-F554, 2007. First published May 30, 2007; doi:10.1152/ajprenal.00156.2007.-Maternal administration of dexamethasone (DEX) for 48 h early in rat kidney development results in offspring with a reduced nephron endowment. However, the mechanism through which DEX inhibits nephrogenesis is unknown. In this study, we hypothesized that DEX may indirectly inhibit nephrogenesis by inhibiting ureteric branching morphogenesis. Whole metanephroi from embryonic day 14.5 (E14.5) rat embryos were cultured in the presence of DEX. DEX (10 Ϫ5 M) exposure for 2 days significantly inhibited ureteric branching compared with metanephroi grown in control media or DEX (10 Ϫ7 M). Culturing metanephroi for a further 3 days (in control media only) reduced total glomerular number in metanephroi previously exposed to DEX (10 Ϫ5 M) or (10 Ϫ7 M) compared with control cultures. Expression of genes known to regulate ureteric branching morphogenesis was determined by real-time PCR in metanephroi after 2 days in culture. DEX exposure in vitro decreased expression of glial cell line-derived neurotrophic factor (GDNF) and increased expression of bone morphogenetic protein-4 (BMP-4) and transforming growth factor-␤1 (TGF-␤1). Similar gene expression changes were found in E16.5 metanephroi in which the dam had been exposed to 2 days of DEX (0.2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) at E14.5/15.5 in vivo. However, in kidneys collected at E20.5 after in vivo exposure for 2 days, GDNF expression was increased and BMP-4 and TGF-␤1 expression decreased suggesting a biphasic response in gene expression to DEX exposure. These results show for the first time that inhibition of ureteric branching morphogenesis may be a key mechanism through which DEX exposure results in a reduced nephron endowment.hypertension; reduced nephron endowment PREDISPOSITION TO MANY adult-onset diseases, including hypertension, is thought to be a result of poor fetal and early postnatal development (1). Maternal glucocorticoid exposure during pregnancy has been used as an animal model to induce a poor in utero environment. Animal models in which the developing fetus is exposed to elevated levels of circulating maternal glucocorticoids result in offspring with a permanent nephron deficit. This reduction in nephron complement is thought to contribute to the onset of hypertension that is also observed in these offspring (12-14, 20, 21). Studies with dexamethasone (DEX), a synthetic glucocorticoid that readily crosses the placental barrier, revealed that the severity of these phenotypes is dependent on the timing and duration of glucocorticoid exposure. Interestingly, just 2 days of exposure is able to produce a decrease in nephron endowment. In the rat, maternal administration of DEX (0.2 mg⅐kg Ϫ1 ⅐day Ϫ1) over 2 days results in adult hypertension and a reduced glomerular (nephron) number in both male and female offspring when administered on embryonic days 15/16 (E15/1...

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Section: Discussionmentioning

confidence: 99%

Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies

Singh¹,

Moritz²,

Bertram³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…In situ hybridization studies using an AT1 receptor riboprobe have identified AT1 receptor mRNA in rat glomeruli, presumably in mesangial cells and the vascular pole (65,68). Quantitative RT-PCR and Northern blot analysis have shown that both AT1A and AT1B receptor mRNAs are expressed in cultured rat mesangial cells, with a predominance of the AT1B isoform (74). This exclusive localization of AT1 receptor and its mRNA expression in mesangial cells is in good accord with functional studies, in which AT1 receptors mediate all known actions of Ang II on intracellular calcium mobilization, prostaglandin (PGE2) production, and protein synthesis in these cells (73,(75)(76)(77).…”

Section: Ang II Receptor Subtypes In Glomerular Mesangiummentioning

confidence: 99%

Localization and Functional Properties of Angiotensin II AT1 Receptors in the Kidney. Focus on Renomedullary Interstitial Cells.

et al. 1997

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The renal medulla plays an important role in maintaining body fluid and electrolyte balance and longterm blood pressure homeostasis through its unique structural and functional properties. Among several humoral, paracrine factors or autocoids, angiotensin II (Ang II) has been implicated in the regulation of renal medullary function, including the medullarylpapillary microcirculation, urine concentration, and blood pressure, but the mechanisms by which Ang II exerts influences in the renal medulla are largely unknown. The purpose of this review is to summarize the cellular localization, regulation, and functional properties of Ang II AT1 receptors in the kidney, with special emphasis on type I renomedullary interstitial cells (RMICs) in the renal medulla and cultured RMICs. High densities of AT1 receptors have been localized in type I RMICs in the inner stripe of the outer medulla by high resolution light and electron microscopic autoradiography following in vitro or in vivo labelling, or in cultured RMICs. Furthermore, reverse transcription polymerase chain reaction and Southern blot analysis now confirm that AT1 receptors in cultured RMICs are exclusively of the AT1A subtype. In cultured RMICs, Ang II markedly increases intracellular inositol 1,4,5-triphosphate (IP3) concentration, and stimulates cell proliferation and extracellular matrix synthesis, and these cellular responses are exclusively mediated by AT1 receptors. Considering the co-occurrence of high levels of renin, renin substrate angiotensinogen, and Ang II in the interstitial fluid compartment, and AT1 receptors in type I RMICs of the renal medulla, the AT1 receptor-bearing RMICs may be more responsive to the locally formed interstitial Ang II than to the circulating peptide. Since RMICs also contain the receptors for other vasoactive peptides, such as endothelin (ETA and ETB), natriuretic peptides (NPRA and NPRB), and bradykinin (B2), and synthesize prostaglandins and medullipins, they may serve as an important site for functional interactions between Ang II and other vasoactive peptides in modulating renal medullary function. More studies using different experimental approaches are therefore required to explore and elucidate the functional role of renal interstitial Ang II and AT1 receptors in RMICs in the physiological control of renal medullary function and in the pathophysiology of hypertension and progressive renal diseases. (Hypertens Res 1997; 20: 233-250)

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“…7,8 An increased cortisol availability within the vascular wall, a known target for glucocorticoids and mineralocorticoids, could be essential for the response to vasoactive mediators, such as the pressor hormones angiotensin II (Ang II) and ␣-adrenergic agonists. 9 Glucocorticoids, such as dexamethasone, have been shown (1) to stimulate Ang II type 1A (AT 1A ) receptor expression via glucocorticoid responsive elements in the gene promotor, 10,11 (2) to enhance AT 1 receptor binding of Ang II in vascular smooth muscle cells, 12 and (3) to reduce AT 2 receptor expression, 13 all of which could also explain the sensitization to Ang II in PE.…”

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confidence: 99%

Fluid Shear Stress Reduces 11β-Hydroxysteroid Dehydrogenase Type 2

et al. 2001

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Abstract-In pregnancy, invading trophoblasts represent the inner vascular border of maternal spiral arteries and are exposed to elevated shear stress (ss) in hypertensive disorders. Intracellular cortisol availability is regulated by 11␤-hydroxysteroid dehydrogenases (11␤-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11␤-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11␤-HSD1; however, 11␤-HSD2 message and activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11␤-HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of ss. cAMP-dependent protein kinase A activation increased the 11␤-HSD2 activity yet did not prevent the ss response. The ss response was completely protein kinase C independent. The mitogen-activated protein kinase kinase inhibitor PD-098059 enhanced 11␤-HSD2 activity in static conditions yet only ameliorated the ss effect. Cytochalasin D disrupts focal adhesion (FA)-cytoskeleton interactions and abolished the ss-induced tyrosine phosphorylation of FA kinase dose-dependently, thus maintaining 11␤-HSD2 activity. The 11␤-HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolished the ss effect on 11␤-HSD2 activity. In conclusion, JEG-3 cells express 11␤-HSD2, which is downregulated by ss. Regulatory mechanisms involve transcriptional control and require intact FA-cytoskeleton signaling and phosphorylation of FA kinase. Thus, ss adds to an enhanced intracellular availability of cortisol, which may ultimately support a vasoconstrictive vascular response. (Hypertension. 2001;37:160-169.)

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Regulation of Angiotensin II Receptor Subtypes by Dexamethasone in Rat Mesangial Cells

Cited by 28 publications

References 32 publications

Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies

Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies

Localization and Functional Properties of Angiotensin II AT1 Receptors in the Kidney. Focus on Renomedullary Interstitial Cells.

Fluid Shear Stress Reduces 11β-Hydroxysteroid Dehydrogenase Type 2

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