A role for angiotensin II AT<sub>1</sub>receptors in ureteric bud cell branching

Iosipiv, Igor V.; Schroeder, Mercedes

doi:10.1152/ajprenal.00401.2002

Cited by 47 publications

(67 citation statements)

References 43 publications

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“…As noted above, increased apoptosis has been hypothesized as a mechanism through which a prenatal perturbation could result in decreased nephron endowment. Blockade of the AT1R has previously been reported to inhibit ureteric branching morphogenesis (16). Our data show differential effect of DEX on the AT1R subtypes, with an increase in AT1Ra and a decrease in AT1Rb.…”

Section: Discussionsupporting

confidence: 64%

“…These last two genes are of great interest as recently, Dickinson et al (10) reported that 60 h of DEX exposure to pregnant Spiny mice increased expression of both BMP-4 and TGF-␤1 in the fetal metanephroi. The renal renin-angiotensin system (RRAS) has also been shown to be important in kidney development with the major receptor the angiotensin II type 1 receptor (AT1R) able to regulate ureteric branching morphogenesis as well as renal growth (16). This is of great importance as maternal DEX exposure alters the expression of fetal angiotensin II receptors in other models of DEX exposure (17).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 64%

mentioning

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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“…Renin mRNA and protein were also found to be expressed at low levels in the connecting tubule of mice during salt restriction (22,23). The presence of renin mRNA in the medulla at least under some circumstances and our evidence for transient medullary activity of the renin promoter during development would add a mechanistic aspect to the notion that angiotensin II may be involved in kidney development and in particular in the morphogenesis of the branching ureteric bud (8). In agreement with this concept, renin-angiotensin system-deficient mouse models are consistently characterized by papillary atrophy and concentrating defects (5,15,32,35).…”

Section: Discussionmentioning

confidence: 52%

Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene

Castrop

Oppermann

Weiss

et al. 2006

Physiological Genomics

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To assess the feasibility of using the renin promoter for expressing Cre recombinase in juxtaglomerular (JG) cells only, we generated five independent transgenic mouse lines (designated hRen-Cre) expressing Cre recombinase under control of a 12.2-kb human renin promoter. In the kidneys of adult mice Cre mRNA (RT-PCR) was found in the renal cortex, with Cre protein (immunohistochemistry) being localized in afferent arterioles and to a lower degree in interlobular arteries. Cre mRNA levels were regulated in a renin-typical fashion by changes in oral salt intake, water restriction, or isoproterenol infusion, indicating the presence of key regulatory elements within 12.2 kb of the 5Ј-flanking region of the human renin gene. hRen-Cre mice were interbred with both the ROSA26-EGFP and ROSA26-lacZ reporter strains to assess renin promoter activity from Cre-mediated excision of a floxed stop cassette and subsequent enhanced green fluorescent protein (EGFP) and ␤-galactosidase (␤-gal) detection. In adult mice, ␤-gal staining and EGFP were observed in afferent arterioles and interlobular arteries, overlapping with Cre protein expression. In addition, intense ␤-gal staining was found in cortical and medullary collecting ducts where Cre expression was minimal. In embryonic kidneys, ␤-gal staining was detected in the developing collecting duct system beginning at embryonic day 12, showing substantial activity of the human renin promoter in the branching ureteric bud. Our data indicate that besides its well-known activity in JG cells and renal vessels the human renin promoter is transiently active in the collecting duct system during kidney development, complicating the use of this approach for JG cell-specific excision of floxed targets. renin; kidney development THE RENIN-ANGIOTENSIN SYSTEM plays a key role in the regulation of body fluid volume and arterial blood pressure. In general, the production and release of the proteolytic enzyme renin by juxtaglomerular (JG) cells is rate limiting for the generation of the bioactive end product angiotensin II. Thus an assessment of the response of the renin-angiotensin system to physiological and pathological challenges requires an understanding of the signaling mechanisms regulating the synthesis and secretion of renin. Investigations of the pathways affecting renin release by JG cells would be greatly aided by cell-specific deletions of individual signaling components. A possible first step to achieve such spatial control of gene expression in JG cells is the identification of a cell-specific promoter that can be utilized to express Cre recombinase in this cell type.In the adult organism, renin is a rather specific marker of JG cells (29,30). Although the enzyme can also be found in low levels in other locations, the renin promoter would therefore appear to be a good candidate to direct robust and selective expression of Cre recombinase to JG cells. Expression of ␤-galactosidase (␤-gal) in a transgenic mouse in which the LacZ gene was placed under the control of a 12.2-kb fragment...

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“…Quantitative analysis of murine Ang II receptors AT 1 R and AT 2 R gene expression indicate that AT 1 R undergo a progressive increase during fetal and neonatal life, whereas AT 2 R are high in the fetus and decline significantly with maturation (11). Immunolocalization studies demonstrated that AT 1 R and AT 2 R are expressed in the UB and its early branches of embryonic day 12 (E12) mouse embryos, whereas angiotensinogen and renin are expressed in the stromal mesenchymal cells that surround the UB branches (12)(13)(14). The localization of RAS components in the stroma and UB provided the initial suggestion that paracrine signaling through RAS-AT receptors may…”

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confidence: 99%

“…In vitro studies have shown further that UB cells that are isolated from E11.5 mouse embryos express AT 1 R that are functionally coupled to the mitogen-activated protein kinase (MAPK) pathway (15). UB cells that are seeded in collagen gels form cellular cords and tubular structures, and treatment with Ang II increases the number and the complexity of these cellular branches (12). Ang II-induced UB cell branching is mediated in part via the AT 1 R because it is abrogated by the specific AT 1 R antagonist candesartan.…”

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confidence: 99%

Angiotensin II Type 1 Receptor–EGF Receptor Cross-Talk Regulates Ureteric Bud Branching Morphogenesis

Yosypiv

Schroeder

El‐Dahr

2006

Journal of the American Society of Nephrology

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Angiotensinogen-, angiotensin-converting enzyme-, and angiotensin II (Ang II) type 1 receptor (AT 1 R)-deficient mice exhibit a dilated renal pelvis (hydronephrosis) and a small papilla. These abnormalities have been attributed to impaired development of the ureteral and pelvic smooth muscle. Defects in the growth and branching of the ureteric bud (UB), which gives rise to the collecting system, have not been examined carefully. This study tested the hypothesis that Ang II stimulates UB growth and branching in the intact metanephros. Immunohistochemistry demonstrated that embryonic mouse kidneys express AT 1 R in the UB and its branches. Embryonic day 11.5 metanephroi were microdissected from Hoxb7-green fluorescence protein mice and grown for 48 h in serum T he metanephros develops via reciprocal inductive interactions between the ureteric bud (UB) and the metanephrogenic mesenchyme (MM) (1,2). Signals from the MM induce UB outgrowth from the nephric duct and its elongation and entrance into the mesenchyme followed by repetitive branching to form the renal collecting system (ureter, pelvis, calyces, and collecting ducts). In turn, emerging UB tips induce surrounding mesenchymal cells to condense, aggregate, undergo mesenchymal-to-epithelial transition, and form nephrons (from the glomerulus to the distal tubule). Therefore, UB branching morphogenesis is critical in determining nephron number, and subtle defects in the efficiency and/or accuracy of this process potentially can have profound effects on the proper development of the metanephric kidney. Decreased nephron endowment is linked to hypertension and eventual progression to chronic renal failure (3,4). In addition, aberrant UB branching morphogenesis causes renal dysplasia, the leading cause of chronic renal failure in human infants.Genetic inactivation of the renin-angiotensin system (RAS) genes in mice causes abnormalities in the development of the ureter, renal pelvis, and papilla (5-9). Angiotensinogen-, angiotensin-converting enzyme (ACE)-, or angiotensin II (Ang II) type 1 receptor (AT 1 R)-deficient mice exhibit pelvic dilation (hydronephrosis) and a small papilla mimicking urinary tract obstruction. Elegant studies from Ichikawa's laboratory have suggested that absence of AT 1 R signaling in ureteral smooth muscle cells impairs pelvic-ureteral smooth muscle development and peristalsis (9). Mutations in the AT 2 R gene in mice and humans are associated with increased incidence of lower urinary tract anomalies, including double ureters and vesicoureteral reflux (10). These findings indicate that UB growth and development are a target for Ang II actions. Work that has performed by several laboratories, including ours, has revealed that the fetal kidney expresses a local RAS. Quantitative analysis of murine Ang II receptors AT 1 R and AT 2 R gene expression indicate that AT 1 R undergo a progressive increase during fetal and neonatal life, whereas AT 2 R are high in the fetus and decline significantly with maturation (11). Immunolocalization studies d...

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A role for angiotensin II AT₁receptors in ureteric bud cell branching

Cited by 47 publications

References 43 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

Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene

Angiotensin II Type 1 Receptor–EGF Receptor Cross-Talk Regulates Ureteric Bud Branching Morphogenesis

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A role for angiotensin II AT1receptors in ureteric bud cell branching

Cited by 47 publications

References 43 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

Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene

Angiotensin II Type 1 Receptor–EGF Receptor Cross-Talk Regulates Ureteric Bud Branching Morphogenesis

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A role for angiotensin II AT₁receptors in ureteric bud cell branching