An Abd-B Class HOX·PBX Recognition Sequence Is Required for Expression from the Mouse Ren-1 Gene

Li, Pan; Xie, Yao; Black, T. Andrew; Jones, Craig; Pruitt, Steven C.; Gross, Kenneth W.

doi:10.1074/jbc.m011541200

Cited by 60 publications

(65 citation statements)

References 44 publications

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“…Two other cAMP response elements have been described in the mouse renin gene. One of them is a CRE element located in the renin enhancer (25), and the other is a HOX/PBX site (RP-2 element) in the proximal promoter (27). However, these elements do not confer full cAMP responsiveness to the renin gene in As4.1 cells (2, 31).…”

Section: Discussionmentioning

confidence: 99%

“…Several transcription factors have been described as potential regulators of renin expression in vitro. These include NF-kB (24), CREB/CREM (25), vitamin D receptor (26), HOX/PBX (27), and many others. However, because the primary culture of JG cells is very difficult due to a rapid decrease of renin expression and a loss in cellular phenotype, most of the evidence is based on in vitro studies of cultured cell lines, only some of them constitutively expressing renin.…”

Section: Discussionmentioning

confidence: 99%

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Liver X receptors and regulate renin expression in vivo

Morello¹

2005

Journal of Clinical Investigation

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The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor α (LXRα) and LXRβ in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXRα functioned as a cAMP-activated factor, LXRβ was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXRα was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXRα to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXRα -/-mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXRβ -/-mice exhibited reduced kidney renin mRNA levels compared with controls. LXRα -/-LXRβ -/-mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXRα and LXRβ regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXRα signaling pathway is required for the adrenergic control of the renin-angiotensin system. IntroductionRenin is an aspartyl protease that catalyzes the cleavage of angiotensinogen to angiotensin I, the first and rate-limiting step of the renin-angiotensin cascade. Circulating renin is expressed in and released from specialized juxtaglomerular (JG) cells strategically located in the afferent arterioles of kidney glomeruli. By regulating the rate of angiotensin generation, renin plays a pivotal physiological role in salt-volume homeostasis and in the control of blood pressure. Increased renin expression and activity is associated with cardiovascular diseases such as hypertension, congestive heart failure, stroke, and kidney disease. Given its key physiological function, renin is highly regulated from transcription to secretion. The transcriptional regulation is particularly critical and complex, functioning through positive and negative regulatory elements located in the promoter and enhancer regions (1). Several transcription factors are capable of binding to these sites and can influence the expression of renin in vitro. However, the in vivo significance of these factors with respect to the physiology and pathophysiology of the renin-angiotensin-aldosterone system (RAAS) is unknown, since most of the current evidence is based on in vitro studies performed on cell lines with limited similarity to kidney JG cells.Using immortalized cell lines, we have previously identified a member of the nuclear hormone receptor family, liver X receptor α

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Liver X receptors and regulate renin expression in vivo

Morello¹

2005

Journal of Clinical Investigation

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“…Renin expression becomes progressively more restricted as the arterial tree branches, until only mature JG cells express the gene expressing cells identified early in renal development are precursors of cells that ultimately differentiate into cell types that do not normally express renin in the adult kidney, but retain the potential to re-synthesize renin when homeostasis is threatened. In establishing a link between the developmental profile of renin expression and transcriptional regulation, Gross and colleagues (42) reported that the Abd-B class of Hox transcription factors (HoxD10 and its binding partner PBX1b) binds to a sequence at Ϫ60 in the proximal promoter and is necessary for maximal renin promoter activity. They also reported that CBF1, a transcriptional repressor converted to an activator by the intracellular domain of notch, and Ets-1, a factor implicated in cellular proliferation and differentiation, both have conserved binding sites in the proximal promoter and regulate renin expression (43).…”

Section: Discussionmentioning

confidence: 99%

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Zhoux

Davis

2006

Journal of Biological Chemistry

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Renin is the rate-limiting enzyme in the renin-angiotensin system and thus dictates the level of the pressor hormone angiotensin-II. The classical site of renin expression and secretion is the renal juxtaglomerular cell, where its expression is tightly regulated by physiological cues. An evolutionarily conserved transcriptional enhancer located 11 kb upstream of the human RENIN gene has been reported to markedly enhance transcription in renin expressing cells in vitro. However, its importance in vivo remains unclear. We tested whether this enhancer is required for appropriate tissue-and cell-specific expression, or for physiological regulation of the human RENIN gene. To accomplish this, we used a retrofitting technique employing homologous recombination in bacteria to delete the enhancer from a 160-kb P1-artificial chromosome containing human RENIN, two upstream genes and one downstream gene, and then generated two lines of transgenic mice. We previously showed that human renin expression in transgenic mice containing the wild type construct is tightly regulated as is expression of the linked genes. Deletion of the enhancer had no effect on tissue-specific expression of human RENIN, but using the downstream gene as an internal control, found that human RENIN mRNA levels were 3-10-fold decreased compared with constructs containing the enhancer. Despite this decrease in expression, renin protein remained localized to renal juxtaglomerular cells and was appropriately regulated by cues that either increase or decrease expression of renin. Our results suggest that sequences other than the enhancer may be necessary for tissue-specific, cell-specific, and regulated expression of human RENIN.Renin is the first and rate-limiting aspartyl protease in the renin-angiotensin system (RAS) 2 cascade that leads to the production of angiotensin-II (Ang-II) by the consecutive cleavage of angiotensinogen by renin and angiotensin-I by angiotensin converting enzyme. Ang-II is an important regulator of cardiovascular function, stimulating vasoconstriction, cardiac output, aldosterone synthesis, and sympathetic activity, thereby directly and indirectly enhancing peripheral vascular resistance and renal tubular water and salt reabsorption. The critical importance of the RAS is evidenced by gene targeted ablation of the RAS genes in mice. The elimination of any RAS gene in mice causes cardiovascular consequences that include hypotension and renal insufficiency, and developmental consequences including postnatal lethality (1-4). The cardiovascular and developmental defects can be complemented in mice by substitution of the mouse RAS with their human orthologs (5) or by targeted expression of Ang-II (6). In humans, genetic defects in the RAS were reported to cause renal tubular dysgenesis, hypotension, and early stillbirth (7). Consequently, both the mouse and human genetic data illustrate the importance of the system both developmentally and in adults.Renin is primarily expressed in renal juxtaglomerular (JG) cells in the wall of the af...

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“…This sequence was identified as a high-affinity binding site for HoxA9-Pbx1 (Shen et al 1997) and differs in the HoxPbx core recognition sequence by 1 bp from an in vivo binding site (Taylor 1998;Pan et al 2001). HoxA9 is a posterior-regulating Hox protein required for proper limb development in mammals and is implicated as a factor in the induction of Acute Myeloid Leukemias (AMLs; Kroon et al 1998;Lawrence et al 1999;Thorsteinsdottir et al 2001).…”

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confidence: 99%

Structure of HoxA9 and Pbx1 bound to DNA: Hox hexapeptide and DNA recognition anterior to posterior

LaRonde-LeBlanc¹,

Wolberger²

2003

Genes Dev.

207

233

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The large family of Hox transcription factors has critical roles in early morphological development and later cell differentiation (McGinnis and Krumlauf 1992;Krumlauf 1994;Lawrence et al. 1996;Magli et al. 1997). Humans have 39 Hox genes arranged in four clusters (HoxAHoxD). The linear arrangement of genes within each cluster facilitates controlled spatial and temporal expression along the anterior-posterior axis of the body (Fig. 1A). Expression of Hox genes in the wrong segment at the wrong time often results in homeotic transformation of that segment (Lamka et al. 1992;Morgan et al. 1992;Duboule 1994a). Hox homeodomains contain identical DNA-base-contacting residues (Fig. 1B) and have very similar DNA sequence specificity, generally preferring a core DNA-binding site containing the sequence 5Ј-TTNAT-3Ј, whose third base depends on the particular Hox protein (Laughon 1991). Cooperative DNA binding with other protein cofactors, such as the PBC family of homeodomain proteins, is thought to enhance the specificity of Hox proteins and thereby allow them to carry out distinct functions (Chan et al. 1994;Chang et al. 1995;Mann and Chan 1996). The PBC family, which includes human Pbx1 and Drosophila Exd, belongs to a class of proteins that contains the TALE (three-aminoacid loop extension)-type homeodomain, so named because of a three-amino-acid insertion between homeodomain residues 23 and 24 in the loop between helices 1 and 2 (Mann 1995;Mann and Chan 1996;Bü rglin 1997). A subset of vertebrate Hox proteins interacts with Pbx1 via a conserved six-amino-acid motif, or hexapeptide, enabling cooperative DNA binding (Chang et al. 1995;Neuteboom et al. 1995;Peltenburg and Murre 1996;Shen et al. 1996Shen et al. , 1997Passner et al. 1999;Piper et al. 1999).Hox proteins required for anterior development are expressed earliest and are restricted to anterior domains. The more posterior proteins are expressed later in development and in more posterior domains (Duboule 1994b;Krumlauf 1994). This character is critical to their in vivo function. In general, when posterior proteins are ex-

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An Abd-B Class HOX·PBX Recognition Sequence Is Required for Expression from the Mouse Ren-1 Gene

Cited by 60 publications

References 44 publications

Liver X receptors and regulate renin expression in vivo

Liver X receptors and regulate renin expression in vivo

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Structure of HoxA9 and Pbx1 bound to DNA: Hox hexapeptide and DNA recognition anterior to posterior

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