Expression of the mouse renin genes (Ren-) and Ren-2) and of the unique rat renin gene was determined in several extra-renal tissues of mice and rats by primer-directed enzymatic amplification of cDNAs. In addition to the adrenal glands, testis, and ovaries, renin tlnscripts are detected in the liver, whole brain, and hypothalamus and, at lower levels, in spleen, thymus, lung, and prostate. Expression of the rat renin gene correlates with that of the mouse Ren-) gene with the notable exception of the submaxillary gand where renin transcripts are found only in mice. The levels of renin transcripts in the liver of females from both species are higher than in males. In mice, the relative levels of Ren-I and Ren-2 transcripts vary widely in different tissues. These results support the hypothesis of a local renin-angiotensin system in multiple extra-renal sites and imply the existence of complex mechanisms of regulation of the renin gene, previously thought to be expressed in a tissue-specific manner.Renin plays an important role in the control ofblood pressure by cleaving angiotensinogen into angiotensin I. Circulating renin, in its active and inactive pro-renin forms, is produced by the juxtaglomerular cells of the kidney. In mice, the submaxillary gland (SMG) constitutes another major source of renin. The observation of renin activity in several other extra-renal tissues (for review, see ref. 1) has led to the suggestion of extra-renal renin-angiotensin systems. However, activity measurements are sometimes ambiguous due to nonspecific renin-like activities of other proteases and the possible contribution of blood-borne renin in tissue samples (1). The synthesis of renin in extra-renal sites has been supported by the detection of renin mRNA in tissues including the adrenal glands, testis, ovaries, brain, and heart (2-6).However, in the latter studies, renin mRNA levels are often close to the limit of detection by RNA blot analysis. Furthermore, the methods of detection used in studies of extrarenal renin gene expression have not allowed discrimination between transcripts of the two mouse renin genes, Ren-J and Ren-2.Strains of laboratory mice can be divided in two categories on the basis of SMG renin expression: Strains, such as BALB/c or C3H, that produce small amounts of SMG renin possess a single renin gene, designated Ren-), which encodes for the circulating enzyme. Strains, such as DBA/2 or Swiss, which have an additional copy of the renin gene, designated Ren-2, exhibit 100-fold higher SMG renin (7)(8)(9)(10) resulting from the higher SMG transcription-of Ren-2. Renin activity is higher in the SMG of males and transcriptional regulation of Ren-) and Ren-2 by androgens has been demonstrated (11). In contrast to the SMG, Ren-) and Ren-2 are transcribed at the same level in kidney juxtaglomerular cells (12).To elucidate the mechanisms underlying tissue-specific expression of the mouse and rat renin genes and the differential expression of the two mouse genes, several tissues have been examined for the pr...
NaDodSO4/PAGE analysis of in vitro translation products of rat submaxillary gland (SMG) mRNAs has revealed an important sexual dimorphism. Moreover, most of the rat male-specific major translation products differ in size from those translated from male mouse SMG mRNAs. To characterize proteins accumulated in the rat SMG under androgen control, a cDNA library was constructed. Here we report the nucleotide sequence of a 0.7-kilobase mRNA that is 1000-3000 times more abundant in male rats than in female rats. The predicted corresponding protein, SMR1, has a molecular weight of 16,000 and contains a signal peptide for secretion and potential signals for glycosylation. An interesting feature of SMR1 is the presence, in a hydrophilic region, of the tetrapeptide Gln-His-Asn-Pro surrounded by two pairs of basic residues that represent potential cleavage sites for maturation enzymes. In rats, the tissue distribution of the SMR1 mRNA is restricted to the SMG and the prostate. Only very low amounts of SMR1 mRNA can be detected in the SMG of male or female mice. Southern blot analysis indicates the presence of three genes in rats but only one in mice. Hypotheses on the physiological role of SMR1-derived peptides in male rats are discussed.A large number of polypeptides with biologically defined properties are synthesized at high levels in the submaxillary gland (SMG) of rodents (1) and particularly of mice. These proteins, including nerve growth factor (NGF), epidermal growth factor (EGF), and renin, share a number of properties. All are synthesized in the same cell type-the granular convoluted tubular (GCT) cells-in response to various hormonal stimuli, in particular to androgens (2). Further, these secretory proteins can be found in the saliva of mice and are synthesized as precursors that become active after posttranslational processing events, possibly involving kallikrein-like proteinases. Some of these kallikrein-like proteinases are also synthesized under androgen-control in the SMG (3).The biological significance of the accumulation of these polypeptides in the SMG of mice and of their release into the saliva is still unclear. Aggressive behavior in male mice results in the release into the blood of large amounts of submaxillary NGF and renin (4,5), providing some evidence that these molecules play a physiological role. But surprisingly, these proteins are not detected in the SMG of related species. For instance, renin, which represents 2% of the SMG proteins in wild-type and most inbred male mice (6) is not found in the SMG of rats (7). This suggests that these SMG-synthesized polypeptides could be related to the especially aggressive behavior of male mice.Attempts to characterize the genes regulated by androgens in the SMG of rats led us to analyze the patterns of in vitro translation products directed by the mRNAs of this tissue. As in mice, an important sexual dimorphism was observed in the rat SMG translation products. Moreover, the major polypeptides accumulated in the two species appeared to be very ...
The Ren‐2 gene encoding the mouse submaxillary gland (SMG) renin was microinjected into the pronuclei of fertilized eggs from mice carrying only the Ren‐1 gene. In addition to the whole transcription unit, the injected DNA contained 2.5 and 3 kb of upstream and downstream flanking sequences, respectively. Three independent transgenic mice lines were obtained; two of them had integrated one copy of the Ren‐2 gene, the last one had integrated five and eleven copies at two independent sites. Independently of the number of Ren‐2 copies integrated, the pattern of Ren‐2 gene expression in all the transgenic mice was identical to that observed in wild‐type animals in which Ren‐1 and Ren‐2 are closely linked on chromosome 1. In particular, the exogenous Ren‐2 gene was only transcribed in the kidney and in the SMG. In the kidney, Ren‐1 and Ren‐2 mRNAs were present at a comparable level, whereas in the SMG Ren‐2 mRNA was at least 100‐fold more abundant than Ren‐1 mRNA. Moreover, Ren‐2 expression in the SMG was positively regulated by androgens. Only one difference between transgenic mice and wild‐type mice carrying the Ren‐2 gene has been observed: the basal level of Ren‐2 transcription in the SMG of transgenic females was lower than in two‐gene strain females. Androgen treatment of transgenic females induced SMG renin mRNA to a level identical to that of transgenic males. This suggests that the basal level of SMG renin mRNA is dependent upon cis‐acting elements which are not present in the microinjected fragment.
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