Disease relevance of Ren2

• We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background [1].
• Hypertensive transgenic rats overexpressing the Ren2 gene express anxiotic behavioral profile. Melatonin show the anti-anxiogenic effect in these TGR rats [2].
• These studies demonstrate that, in the absence of Ren1(d), Ren2 preserves normal kidney development and prevents severe hypotension [3].
• Chimeric genes containing the 5'-flanking regions of the mouse renin genes, Ren1 and Ren2, associated with the early region of the simian virus 40 (SV40) were constructed [4].
• Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat [5].
• Effects of angiotensin II subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic reticulum Ca2+ handling in hypertensive transgenic rats overexpressing the Ren2 gene [6].

High impact information on Ren2

• The renin regulatory locus (Rnr) is a genetic element governing mouse submaxillary gland (SMG) renin levels [7].
• The renin cDNA clone has also been used in Southern blot analyses to study the organization of homologous DNA sequences in strains carrying different alleles at the Rnr locus [7].
• Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene [8].
• The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2 [9].
• Expression of the DBA/2J Ren-2 gene in the adrenal gland of transgenic mice [10].

Chemical compound and disease context of Ren2

• There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05) [5].
• Nifedipine, losartan and captopril effects on hyperplasia of vascular smooth muscle from Ren-2 transgenic rats [11].
• Angiotensin II mediates cell hypertrophy in vascular smooth muscle cultures from hypertensive Ren-2 transgenic rats by an amiloride- and furosemide-sensitive mechanism [12].
• Without affecting blood pressure or blood glucose, tranilast treatment was associated with a 83% reduction in tubulointerstitial fibrosis (p < 0.001), a 58% reduction in tubular atrophy (p < 0.01) and near normalization of albuminuria (p < 0.05) in diabetic Ren-2 rats [13].

Biological context of Ren2

• Southern analysis of mice from the second generation revealed that the mutant Ren1 and Ren2 were interchromosomally recombined at the loxP sites to produce a new dually mutated allele on the chromosome at the rate of 9.6% (7/73) [14].
• Thyroxine and testosterone transcriptionally regulate renin gene expression in the submaxillary gland of normal and transgenic mice carrying extra copies of the Ren2 gene [15].
• Acute administration of losartan decreases blood pressure further, suggesting a role for Ren2 protein in blood pressure homeostasis [3].
• To distinguish the contributions of Ren1(d) and Ren2 to kidney development and blood pressure homeostasis, we placed green fluorescent protein (GFP) under control of the Ren1(d) renin locus by homologous recombination in mice [3].
• We have previously shown that strains with high levels of SMG renin, such as Swiss or AKR mice, have two renin genes, Rn1 and Rn2, per haploid genome, while strains with low levels of SMG, such as BALB/c or C57Bl/6, have only one renin gene [16].

Anatomical context of Ren2

• The two recombinant genes which contain, respectively, 0.45- and 2.5-kb the Ren1 and Ren2 5'-flanking sequences, named Ren1Tag and Ren2Tag, were microinjected into fertilized eggs [4].
• Ren-2 is clearly expressed in kidney, SMG and testes [17].
• Furthermore, 5'-flanking sequences of Ren-2, placed upstream of the thymidine kinase or SV40 early region promoters do not alter the activity of these promoters in three different cell lines [18].
• It is intriguing that Ren-2, the duplicated mouse renin gene, is expressed to high levels in the male salivary gland and also contains a transposed intracisternal A-particle genome [19].
• Organs that are involved in cardiovascular regulation, such as the adrenal gland, kidney, and brain, express the Ren-2 gene before hypertension has developed, consistent with the possibility of a causal relationship between transgene expression in these tissues and hypertension [20].

Associations of Ren2 with chemical compounds

• Expression of the mouse renin genes (Ren1 and Ren2) in the submaxillary gland of female mice has been analyzed following administration of thyroxine (T4) or dihydrotestosterone (DHT) [15].
• Chronic losartan treatment results in compensation via recruitment of both Ren1(d)- and Ren2-expressing cells along the preglomerular vessels [3].
• The Ren-1 locus of mice encodes the protease renin, which with converting enzyme processes angiotensinogen to the potent vasopressor angiotensin II [21].
• Male Ren2 (6-7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk [5].
• Systolic blood pressures were measured in conscious male Cyp1a1-Ren2 rats (n = 6) during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.15%, wt/wt), for 14 days [22].

Enzymatic interactions of Ren2

• This enzyme, isolated from the mouse submandibular gland, is also known as prorenin-converting enzyme and cleaves submandibular gland Ren-2 prorenin to yield active renin [23].

Regulatory relationships of Ren2

• The data indicate that submandibular gland renin cross-reacts with kidney renin, but that genetic controls of these polypeptides in the two organs are independent [24].
• Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene [25].

Other interactions of Ren2

• To test this hypothesis, we ablated renin-expressing cells during development by placing diphtheria toxin A chain (DTA) under control of the Ren1d mouse renin promoter by homologous recombination in a two-renin gene strain (Ren2 and Ren1d) [26].
• Recombination between Rnr, a gene that mediates the susceptibility of submaxillary gland renin to induction by androgen, and Dip-1, a chromosome 1 marker, was found in only 1 of 51 recombinant inbred strains, indicating that the two genes are closely linked on chromosome 1 [27].
• Neither glomerular filtration rate nor renal plasma flow was altered in Cyp1a1-Ren2 rats with salt-sensitive hypertension [22].
• Tissue kallikrein mK13 was confirmed to be a prorenin-converting enzyme; and mK9, which was earlier shown to be an EGF-binding protein, was found to cleave mouse Ren 2 prorenin specifically and convert it to mature renin with an activity of approximately 1/10 of that of mK13 [28].
• The catalytic specificity of mGK-13 for Ren-2 prorenin was studied by modeling a prorenin-derived peptide into the active site of mGK-13 [23].

Analytical, diagnostic and therapeutic context of Ren2

• The effects of DHT and T4 were also analyzed in transgenic mice obtained by microinjection of the Ren2 gene [15].
• Sequence analysis of a 319 bp renin cDNA recombinant isolated from a kidney library from the two-gene strain DBA/2Ha corresponds to a transcript of the Ren-1 gene [21].
• In this study, an enzyme which specifically cleaves mouse Ren 2 prorenin at the paired basic residues has been purified from mouse submandibular gland by CM-Toyopearl chromatography, antipain-Sepharose chromatography, and isoelectric focusing [29].
• We have used gene targeting to discover the effects of inactivating the duplicated (Ren-2) gene in strain 129 mice, and we show that mice lacking the Ren-2 gene are viable and healthy [30].
• In this study, a direct ELISA for Ren-2 renin (SMG renin) was established by a sandwich method [31].

References