Granulation Rescue and Developmental Marking of Juxtaglomerular Cells Using “Piggy-BAC” Recombination of the Mouse RenLocus

Mullins, L. J.; Payne, Catherine; Kotelevtseva, Nina; Brooker, Gillian; Fleming, Stewart; Harris, Stephen; Mullins, John J.

doi:10.1074/jbc.m007315200

Cited by 28 publications

(21 citation statements)

References 35 publications

(13 reference statements)

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“…In REKO mice, there was hyperplasia of the macula densa, presumably a compensatory response attempting to increase signaling to JG cells to increase renin secretion and gene expression (1). Macula densa hyperplasia and hypertrophy are also seen in mice lacking Ren-1 c (5) or Ren-1 d (39). In contrast to kidneys of Ren-1 c null mice, however, REKO kidneys did not show hydronephrosis.…”

Section: Discussionmentioning

confidence: 80%

See 1 more Smart Citation

Renin Enhancer Is Critical for Control of Renin Gene Expression and Cardiovascular Function

Adams¹,

Head²,

Markus³

et al. 2006

J. Biol. Chem.

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The important cardiovascular regulator renin contains a strong in vitro enhancer 2.7 kb upstream of its gene. Here we tested the in vivo role of the mouse Ren-1 c enhancer. In reninexpressing As4.1 cells stably transfected with Ren-1 c promoter with or without enhancer, expression of linked ␤-geo reporter, stable expression, and colony formation were dependent on the presence of the enhancer. We then generated mice carrying a targeted deletion of the enhancer (REKO mice) and found marked depletion of renin in renal juxtaglomerular and submandibular ductal cells, as well as hyperplasia of macula densa cells. Plasma creatinine was increased, but electrolytes were normal. Male REKO mice implanted with telemetry devices had 9 ؎ 1 mm Hg lower mean arterial pressure ( p < 0.001), which was partly normalized by a high NaCl diet. Locomotor activity was lower, and baroreflex sensitivity was normal. Markedly reduced mean arterial pressure variability in the midfrequency band indicated a contribution of reduced sympathetic vasomotor tone to the hypotension. In conclusion, the renin enhancer is critical for renin gene expression and physiological sequelae, including response to alteration in salt intake. The REKO mouse may be useful as a low renin expression model. Renin, produced in renal juxtaglomerular (JG) 4 cells, is the rate-limiting enzyme of the renin-angiotensin system that generates angiotensin II. The renin-angiotensin system helps maintain fluid and electrolyte balance and blood pressure (BP) but also has important roles in development, vascular hypertrophy, angiogenesis, and clinical conditions, such as renal hypertension and heart failure (1). The JG cells are modified myoepithelial cells in the wall of the afferent arteriole and are in close contact with the macula densa segment of the distal tubule that signals the renal arterioles to regulate glomerular filtration rate and renin secretion (2).Transcription of renin genes is regulated in both a tissuespecific and developmental manner (1, 3). In the mouse kidney, renin expression is first detected at embryonic day 14.5 in the developing arteries and renal arterial branches. Expression then becomes progressively restricted to smaller arteries and arterioles, eventually contracting to just the JG cells postpartum (4). In addition to the kidney, mice also express renin in the submandibular gland (SMG) and, at lower levels, in adrenal, brain, and various other tissues.To ascertain the importance of renin, strains of mice have been generated with deletion of the entire renin gene (termed Ren-1 c or Ren-1 d , depending on mouse strain). Ren-1 c null mice show neither detectable plasma renin activity nor plasma angiotensin I, a reduction in BP of 20 -30 mm Hg, increased urine output and water intake, and altered renal morphology (5), as also seen in angiotensinogen-deficient mice (6, 7). Consistent with this, Ren-1 d null mice show altered macula densa morphology, complete absence of JG cell granulation, and sexually dimorphic hypotension (8).An understanding of t...

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Section: Discussionmentioning

confidence: 80%

“…A complete lack of renin granulation has been observed in JG cells of mice after deletion of the entire Ren-1 d gene (39). In REKO mice, there was hyperplasia of the macula densa, presumably a compensatory response attempting to increase signaling to JG cells to increase renin secretion and gene expression (1).…”

Section: Discussionmentioning

confidence: 99%

Renin Enhancer Is Critical for Control of Renin Gene Expression and Cardiovascular Function

Adams¹,

Head²,

Markus³

et al. 2006

J. Biol. Chem.

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“…Accordingly, the protogranules often contain paracrystalline cores (862). In mice with two renin genes (Ren-1D and Ren-2), the deletion of Ren-1D, but not Ren-2, is associated with a complete absence of the dense-core secretory granules in JG cells (163,607), suggesting that the ability to form the dense-core secretory vesicles depends on the structural characteristics of the Ren-1 protein. These characteristics may be related to the glycosylation of the protein because renin originating from the Ren-1D gene has three N-linked glycosylation sites, while the Ren-2-derived renin has none.…”

Section: Renin Secretory Vesiclesmentioning

confidence: 99%

Physiology of Kidney Renin

Castrop

Höcherl

Kurtz

et al. 2010

Physiological Reviews

232

277

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The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).

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“…Both Ren-1 and Ren-2 are found in the kidney, 5 though Ren-2 also exists at some nonrenal sites. 9,10 Mice lacking a functional Ren-1 d gene have no JG-cell granulation and exhibit atypical macula densa morphology, 5,11 whereas blood pressure in females is lower (though it is similar in males). 5 In the absence of Ren-1, plasma active renin is reduced, whereas inactive prorenin is increased, suggesting that Ren-1 d is a prerequisite for the formation of renin storage granules despite the presence of Ren-2-generated renin, and further that renin from Ren-1 and Ren-2 genes is secreted through different pathways.…”

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confidence: 99%

Cardiovascular and Renal Phenotype in Mice With One or Two Renin Genes

et al. 2004

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Abstract-We compared the phenotype of two common mouse models, C-57BL/6J (C57), which carries only the Ren-1 c gene, and 129/SvJ (Sv-129), with both Ren 1 d and Ren-2. We hypothesized two renin gene Sv-129 would have increased blood pressure and the renin-angiotensin system would be more influential in regulating renal function compared with one renin gene mice. Sv-129 consistently had higher blood pressure than C-57, whether conscious (128 versus 108 mm Hg, PϽ0.001) or anesthetized (102 versus 88 mm Hg, PϽ0.001). Plasma renin concentration in both conscious and anesthetized C-57 mice was 3-to 4-fold higher than in Sv-129 (PϽ0.05), whereas renal cortical renin content was 2.5-fold higher (PϽ0.005). Renal blood flow and renal vascular resistance were the same in C-57 and Sv-129. Exogenous angiotensinogen produced identical pressor and renal vasoconstrictor responses in both strains. Blocking AT 1 receptors with losartan reduced blood pressure by 19 mm Hg in both strains. Nitric oxide synthase inhibition by L-NAME increased blood pressure by 29 mm Hg in C-57 and 35 mm Hg in Sv-129 mice, but the decrease in renal blood flow was 30% less in C-57 (PϽ0.025). We conclude that Sv-129 mice with two renin genes have higher blood pressure but lower plasma and renal renin than C-57 mice with one renin gene. Renin substrate may limit angiotensin II production in the mouse. In Sv-129, the influence of nitric oxide on renal but not systemic resistance may be exaggerated. Renin from Ren-2 may act independently of normal renin control mechanisms. Key Words: angiotensin Ⅲ angiotensinogen Ⅲ endothelium Ⅲ mouse Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ renin T he potent vasoconstrictor hormone angiotensin II (AngII) is the active product of the renin-angiotensin system. AngII is typically produced through the rate-limiting cleavage of the substrate angiotensinogen by the enzyme renin.

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Granulation Rescue and Developmental Marking of Juxtaglomerular Cells Using “Piggy-BAC” Recombination of the Mouse RenLocus

Cited by 28 publications

References 35 publications

Renin Enhancer Is Critical for Control of Renin Gene Expression and Cardiovascular Function

Renin Enhancer Is Critical for Control of Renin Gene Expression and Cardiovascular Function

Physiology of Kidney Renin

Cardiovascular and Renal Phenotype in Mice With One or Two Renin Genes

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