Preservation of Intracellular Renin Expression Is Insufficient to Compensate for Genetic Loss of Secreted Renin

Interdisciplinary Genetics Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Hypertension (Impact Factor: 6.48). 10/2009; 54(6):1240-7. DOI: 10.1161/HYPERTENSIONAHA.109.138677
Source: PubMed


The primary product of the renin gene is preprorenin. A signal peptide sorts renin to the secretory pathway in juxtaglomerular cells where it is released into the circulation to initiate the renin-angiotensin system cascade. In the brain, transcription of renin occurs from an alternative promoter encoding an mRNA starting with a new first exon (exon 1b). Exon 1b initiating transcripts skip over the classical first exon (exon 1a) containing the initiation codon for preprorenin. Exon 1b transcripts are predicted to use a highly conserved initiation codon within exon 2, producing renin, which should remain intracellular, because it lacks the signal peptide. To evaluate the roles of secreted and intracellular renin, we took advantage of the organization of the renin locus to generate a secreted renin (sRen)-specific knockout, which preserves intracellular renin expression. Expression of sRen mRNA was ablated in the brain and kidney, whereas intracellular renin mRNA expression was preserved in fetal and adult brains. We noted a developmental shift from the expression of sRen mRNA in the fetal brain to intracellular renin mRNA in the adult brain. Homozygous sRen knockout mice exhibited very poor survival at weaning. The survivors exhibited renal lesions, low hematocrit, an inability to generate a concentrated urine, decreased arterial pressure, and impaired aortic contraction. These results suggest that preservation of intracellular renin expression in the brain is not sufficient to compensate for a loss of sRen, and sRen plays a pivotal role in renal development and function, survival, and the regulation of arterial pressure.

Download full-text


Available from: Justin L Grobe, Aug 14, 2014
11 Reads
  • Source
    • "They found renin promoter activity in the neurons of the cerebellum and hippocampus and in the cardiovascular regulatory regions such as the rostral ventrolateral medulla (RVLM), the subfornical organ (SFO), the paraventricular nucleus (PVN), and the supraoptic nucleus (SON). This group also discovered two different forms of renin in the brain, the intracellular (icRenin) and secret (sRenin) renin, derived from two different renin transcripts [34]. The relevance of icRenin is still unclear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It is well known that the brain renin-angiotensin (RAS) system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang) II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance. It then focus on the (pro)renin receptor (PRR), a newly discovered component of the RAS which has a high level in the brain. We review the role of prorenin and PRR in peripheral organs and emphasize the involvement of brain PRR in the pathogenesis of hypertension. Some future perspectives in PRR research are heighted with respect to novel therapeutic target for the treatment of hypertension and other cardiovascular diseases.
    International Journal of Hypertension 12/2012; 2012:290635. DOI:10.1155/2012/290635
  • Source
    • "Such ligands can be synthesized and targeted to the Golgi apparatus for secretion or act intracellularly either before secretion or following reuptake. The intracrine gene product might also arise from an alternative transcription initiation site, differences in mRNA maturation or translation leading to a gene product lacking secretory signals and consequently active only in the intracellular space (Figure 4) (Kiefer et al., 1994; Lee-Kirsch et al., 1999; Xu et al., 2009). To this extent, it is interesting to note that two isoforms of the human UII precursor, differing mostly by their peptide signal, were discovered (Coulouarn et al., 1998; Ames et al., 1999). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The urotensinergic system plays central roles in the physiological regulation of major mammalian organ systems, including the cardiovascular system. As a matter of fact, this system has been linked to numerous pathophysiological states including atherosclerosis, heart failure, hypertension, diabetes as well as psychological, and neurological disorders. The delineation of the (patho)physiological roles of the urotensinergic system has been hampered by the absence of potent and selective antagonists for the urotensin II-receptor (UT). Thus, a more precise definition of the molecular functioning of the urotensinergic system, in normal conditions as well as in a pathological state is still critically needed. The recent discovery of nuclear UT within cardiomyocytes has highlighted the cellular complexity of this system and suggested that UT-associated biological responses are not only initiated at the cell surface but may result from the integration of extracellular and intracellular signaling pathways. Thus, such nuclear-localized receptors, regulating distinct signaling pathways, may represent new therapeutic targets. With the recent observation that urotensin II (UII) and urotensin II-related peptide (URP) exert different biological effects and the postulate that they could also have distinct pathophysiological roles in hypertension, it appears crucial to reassess the recognition process involving UII and URP with UT, and to push forward the development of new analogs of the UT system aimed at discriminating UII- and URP-mediated biological activities. The recent development of such compounds, i.e. urocontrin A and rUII(1-7), is certainly useful to decipher the specific roles of UII and URP in vitro and in vivo. Altogether, these studies, which provide important information regarding the pharmacology of the urotensinergic system and the conformational requirements for binding and activation, will ultimately lead to the development of potent and selective drugs.
    Frontiers in Endocrinology 01/2012; 3:174. DOI:10.3389/fendo.2012.00174
  • Source
    • "Intracrine ligands can be synthesized and targeted to the Golgi apparatus for secretion; however, they may also act intracellularly either before or after secretion (following reuptake; Re, 1999). In the case of peptide agonists, the intracrine gene product might arise from an alternative transcription initiation site, differences in mRNA maturation or translation leading to a gene product lacking secretory signals and consequently active only in the intracellular space (Kiefer et al. 1994; Lee-Kirsch et al. 1999; Xu et al. 2009). Alternative splicing can result in the generation of peptides that lack ER signal sequences or contain an altered hydrophobic sequence. "
    [Show abstract] [Hide abstract]
    ABSTRACT: G protein-coupled receptors (GPCRs) play key physiological roles in numerous tissues, including the heart, and their dysfunction influences a wide range of cardiovascular diseases. Recently, the notion of nuclear localization and action of GPCRs has become more widely accepted. Nuclear-localized receptors may regulate distinct signalling pathways, suggesting that the biological responses mediated by GPCRs are not solely initiated at the cell surface but may result from the integration of extracellular and intracellular signalling pathways. Many of the observed nuclear effects are not prevented by classical inhibitors that exclusively target cell surface receptors, presumably because of their structures, lipophilic properties, or affinity for nuclear receptors. In this topical review, we discuss specifically how angiotensin-II, endothelin, β-adrenergic and opioid receptors located on the nuclear envelope activate signalling pathways, which convert intracrine stimuli into acute responses such as generation of second messengers and direct genomic effects, and thereby participate in the development of cardiovascular disorders.
    The Journal of Physiology 12/2011; 590(Pt 6):1313-30. DOI:10.1113/jphysiol.2011.222794 · 5.04 Impact Factor
Show more