Differential extra-renal expression of the mouse renin genes

Miller, Christopher C.J.; Carter, Andrew T.; Brooks, Jeanie I.; Lovell-Badge, Robin; Brammar, William J.

doi:10.1093/nar/17.8.3117

Cited by 46 publications

(12 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All three genes display overlapping but distinct tissue specificities (1, 3, 15). In addition, mouse strains have been created that contain Ren-JC and a transgenic Ren-2 (2, 34) and Ren-IC and a transgenic Ren-JD (3). Recently, Mullins et al (35) have produced transgenic rats harboring Ren-2.…”

Section: Discussionmentioning

confidence: 99%

“…13; unpublished results). The three mouse renin genes display similar but distinct tissue specificities (1,3,14,15) (Fig. 1) gg of linearized pTk-Ren-neo at 500 OLF and 250 V in a 0.4-cm pathlength electroporation chamber (Bio-Rad).…”

Section: Introductionmentioning

confidence: 99%

“…13; unpublished results). The three mouse renin genes display similar but distinct tissue specificities (1,3,14,15) and similar developmental expression profiles (16).…”

mentioning

confidence: 99%

“…However, a number of other extrarenal sites of renin biosynthesis have now been described, including the adrenal gland, liver, and testes (1)(2)(3). The function of this extrarenal renin is not known.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Targeted integration of the Ren-1D locus in mouse embryonic stem cells.

Miller¹,

McPheat²,

Potts³

1992

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We have introduced a Ren-ID targeting vector Into embryonic stem cells containing the two highly homologous mouse renin genes Ren-ID and Ren-2. Using a polymerase chain reaction (PCR) screen designed to detect targeted integration at Ren-ID and Ren-2, we isolated 15 targeted embryonic stem cell clones, all of which had undergone a gene conversion event at the Ren-iD locus. We did not isolate any clones in which the incoming DNA had recombined with Ren-2. Over the region encompassed by our transgene, Ren-ID and Ren-2 display >95% homology. Our results suggest that the machinery driving gene targeting by means of homologous recombination in mammalian cells is capable of dis hing between these two sequences. Construction of transgenic mice with the embryonic stem cells reported here carrying a mutated renin gene will permit a greater understanding of the functions of the Ren-iD and Ren-2 gene products and their relative contribution to cardiovascular homeostasis.Renin is an aspartyl protease that catalyzes the initial and rate-limiting step in the conversion of angiotensinogen to the potent vasoactive hormone angiotensin II. The primary site of synthesis ofcirculating renin is thejuxtaglomerular cells of the kidney. However, a number of other extrarenal sites of renin biosynthesis have now been described, including the adrenal gland, liver, and testes (1-3). The function of this extrarenal renin is not known.In mice, high levels of renin and renin mRNA can also be found in the submandibular gland (4, 5). Mice are polymorphic for the number of renin genes, certain inbred strains harboring one gene (Ren-JC) and others containing two genes (Ren-JD and Ren-2). The mouse renin genes are located on chromosome 1 (6), with the Ren-2 gene situated -20 kilobases (kb) upstream ofRen-JD (relative to the transcriptional direction) in two-gene animals; both genes are transcribed in the same direction (7). The presence of the Ren-2 gene appears to be the result of a duplication of the renin locus t3-10 million years ago (8, 9). DNA sequence features unique to Ren-2 include the presence of a proviral intracisternal A particle located downstream and a B2 repetitive element situated upstream of Ren-2 (10, 11). However, Ren-JD and Ren-2 display a high degree of homology across the structural region of the gene having the same genomic organization (9,12,13) and sharing >96% sequence identity at the level of the transcript (9). At the genomic level (including intronic sequences) Ren-JD and Ren-2 share -95% sequence identity (ref. 13; unpublished results). The three mouse renin genes display similar but distinct tissue specificities (1,3,14,15) (Fig. 1) gg of linearized pTk-Ren-neo at 500 OLF and 250 V in a 0.4-cm pathlength electroporation chamber (Bio-Rad). These cells were then plated out on ten 9-cm Petri dishes. Selection with G418 (250 Ag/ml) and gancyclovir (2 puM) was applied after Abbreviation: ES, embryonic stem. tTo whom reprint requests should be sent at present address:

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…13; unpublished results). The three mouse renin genes display similar but distinct tissue specificities (1,3,14,15) and similar developmental expression profiles (16).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Targeted integration of the Ren-1D locus in mouse embryonic stem cells.

Miller¹,

McPheat²,

Potts³

1992

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…It has therefore been difficult to dissect the individual roles of each gene to date or to determine if renin-1 d and renin-2 play functionally equivalent roles in vivo. For example, Ren-1 d and Ren-2 are expressed at equivalent levels in JG cells, but Ren-2 is expressed at high levels (2% of total SMG protein) in the submandibular gland and is under the control of various hormones, including testosterone, whereas Ren-1 d is only detectable at trace levels in this organ (9). The evolution of non-identical, tightly regulated developmental expression pro-files, and the biochemical differences between renin-1 and renin-2 proteins, suggest that the two genes may indeed possess functionally distinct properties.…”

mentioning

confidence: 99%

Renin-1 Is Essential for Normal Renal Juxtaglomerular Cell Granulation and Macula Densa Morphology

Clark¹,

Sharp²,

Morley³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

The secretion of renin from granules stored in renal juxtaglomerular cells plays a key role in blood pressure homeostasis. The synthesis and release of renin and the extent of granulation is regulated by several mechanisms including signaling from the macula densa, neuronal input, and blood pressure. Through the use of a gene-targeting vector containing homology arms generated using the polymerase chain reaction, we have inactivated the Ren-1 d gene, one of two mouse genes encoding renin, and report that lack of renin-1 d results in altered morphology of the macula densa of the kidney distal tubule and complete absence of juxtaglomerular cell granulation. Furthermore, Ren-1 d؊/؊ mice exhibit sexually dimorphic hypotension. The altered growth morphology of the macula densa in Ren-1 d -null mice should provide a tool for the investigation of the JG cell-macula densa signaling. Furthermore, the current data indicate that expression of the Ren-1 d gene is a prerequisite for the formation of storage granules, even though the related protein renin-2 is present in these mice, suggesting that renin-1 d and renin-2 are secreted by distinct pathways in vivo.Renin (EC 3.4.23.15) is an aspartyl protease, which catalyzes the first step in the renin angiotensin system, the end product of which is the potent vasopressor peptide hormone, angiotensin II (AngII).1 This octapeptide acts to increase peripheral vascular resistance and promote salt and fluid retention in concert with the hormone aldosterone. Renin is synthesized principally in the kidney juxtaglomerular (JG) cells, a group of modified smooth muscle cells located at the distal end of the renal afferent arteriole of the glomerulus (1). JG cells are in close contact with the macula densa, a specialized plaque of epithelial cells of the kidney distal tubule, which signal to the renal arterioles to regulate glomerular filtration rate and the secretion of renin, in response to ionic concentration and flow rate in the distal tubule (2, 3), the so-called tubuloglomerular feedback loop. Except for the submandibular gland (SMG) of the mouse, the JG cells are the only site where prorenin, the inactive zymogen, is known to be converted to the active form of renin. SMG renin does not, however, make its way into the plasma in large quantities and is thought not to play a significant role in blood pressure regulation under normal circumstances (reviewed in Bing et al. (4)). The release of renin from JG cells is mediated by two pathways: regulated release of the mature, active renin from modified lysosomal storage granules and constitutive release of the inactive zymogen. While the regulated pathway of renin secretion is responsive to baroreceptor, neurogenic, and macula densa signals (5), the physiological significance of the constitutive secretion of prorenin is not understood, nor are the molecular pathways that link secretory signals to renin maturation and release. Clarification of the mechanisms underlying these processes will be crucial to our understanding of the control of ...

show abstract