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Renin

Brian J. Morris

10.1002/cphy.cp070301

Source: Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance

Originally published: 2000

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 The Renin Paper
1.1 A blood pressure‐raising substance is formed in the kidneys and passed into the blood
1.2 Time course of the pressure elevation following injection of renin
1.3 Analysis of the mechanism underlying the pressure rise
2 Renin Release Regulation
3 Renin Gene: Structure and Control
3.1 Background
3.2 Renin Gene Structure
3.3 Renin Promoter Structure
3.4 Renin Promoter Control
3.5 Transcription Factors
3.6 Renin Messenger RNA
4 Synthesis and Activation
4.1 Biosynthesis of Prorenin
4.2 Processing of Prorenin
4.3 Structure of Renin
4.4 Binding Protein(s) of Renin
5 Genetic Studies
5.1 Studies in Rats
5.2 Studies in Humans
6 Transgenic Mice and Rats
6.1 Human Gene in Mice
6.2 Renin Promoter–Simian Virus 40 T Antigen Transgenic Mice
6.3 Human Promoter Transgenic Mice
6.4 Ren‐2 Hypertensive Transgenic Rats
6.5 Model of Malignant Hypertension
6.6 Renin and Angiotensinogen Transgenic Mice and Rats
6.7 Knockouts
7 Summary and Challenges
Figure 1. Figure 1.

Overall control of human renin production by cyclic adenosine monophosphate (cAMP), involving stimulation of renin secretion from storage granules and of renin synthesis. The latter is directed at both the level of transcription and the level of renin mRNA 205. The effect on mRNA is important but indirect, involving an action of the cAMP pathway on another gene, leading to synthesis of a protein that stabilizes the renin mRNA, thus lengthening its halflife in the cell and boosting synthesis. For more details of the direct action on the renin promoter, see Figure 4.
Figure 2. Figure 2.

Mouse renin genes. a: Molecular arrangement in two‐and one‐gene mice. J and vertical arrow indicate duplication junction. Horizontal arrows show the major transcription‐start site of each gene, as well as direction of transcription. Also shown are DNA insertions: intracisternal A particle (IAP) and mouse insertion‐1 (M1), as well as a heterothyro tropic factor (HFT) island in the 3′‐flanking DNA of each gene. The region indicated by the pentagon immediately upstream of each gene is enlarged in b. b: Enlargement of proximal 5′‐flanking DNA, showing the location of the common insertion relative to the rat and human renin genes, as well as the additional insertions in mouse Ren‐2: 5′, a 143 bp insertion, and, within the common insertion, a type‐2 Alu‐like repeat element. Triangles at ends of boxes refer to direct repeat sequence bordering the insertion site.
Figure 3. Figure 3.

Physiologically relevant functional elements associated with human and mouse renin genes, including far‐upstream enhancer that together with the Pit‐1‐like sequence in proximal promoter DNA is required to achieve normal activity of the renin promoter. A classical silencer element also exists in intron 1. Regulatable expression is mediated via an action of cyclic adenosine monophosphate (cAMP) response element (CRE)–binding protein (CREB) on the CRE (see Fig. 4 for details on the mechanism involved). Part of the cAMP response also involves the Pit‐1‐like site via a CREB‐independent mechanism 124, 462.
Figure 4. Figure 4.

Hypothesis for mechanism by which cyclic adenosine monophosphate (cAMP) mediates physiological control of the human renin gene. Experiments have shown that in renin‐synthesizing cells an increase in cAMP activates protein kinase A (PKA), which in turn phosphorylates cAMP response element‐binding protein (CREB), causing it to bind to the cAMP response element (CRE). This appears to involve a CREB‐activating transcription factor‐1 (ATF‐1) heterodiner or CREB homodimer 124, 462. In unstimulated cells, ATF‐1 is phosphorylated and, by binding to the CRE, may suppress the promoter. The fact that the CRE has low binding affinity coupled with the low phosphorylation of CREB, its ability to undergo rapid deposphorylation, as well as the capacity for greatly enhanced responsiveness of the promoter under conditions that cause CREB‐1 phosphorylation provides a mechanism for establishing a considerable regulatable response range for transcription of the renin gene under various physiological conditions 462. Since PKA and Ca2+/calmodulin‐dependent protein kinases selectively phosphorylate CREB and AFT‐1, possible that a mechanism exists for the convergence and integration of multiple extracellular signals that stimulate (via cAMP) or inhibit (via Ca2+/calmodulin) renin gene expression in renin‐expressing cells in vivo. ℗ is phosphorylation site.
Figure 5. Figure 5.

Renin precursor and processing sites in mouse, rat, and human (not drawn to scale). Initial hydrolysis of the N‐terminal signal (pre) peptide occurs prior to completion of synthesis of the nascent protein (site indicated by small arrow nearer left end of polypeptide chain in each case). Question mark at the rat signal peptide–cleavage site and the range of values for amino acids in rat pre and pro fragments indicate uncertainty as to the actual site of hydrolysis. After completion of synthesis of the precursor (prorenin), activation in vivo is achieved by hydrolysis at the site indicated by the large vertical arrow. (This differs for rat because rat prorenin has a lysine instead of an arginine at the activation site that is used in the other species.) At least a portion of the active renin is later cleaved at the site shown by the small arrow toward the right side of the polypeptide chain, to give active two‐chain renin. The position of this cleavage differs for humans and in humans the two‐chains produced are not held together by disulfide bridges (‐S—S‐), as is the case for mice and rats. Numbers preceded by + indicate amino acid number with respect to the first amino acid of the mature protein, designated +1. Numbers followed by aa indicate the amino acid number in each polypeptide segment.


Figure 1.

Overall control of human renin production by cyclic adenosine monophosphate (cAMP), involving stimulation of renin secretion from storage granules and of renin synthesis. The latter is directed at both the level of transcription and the level of renin mRNA 205. The effect on mRNA is important but indirect, involving an action of the cAMP pathway on another gene, leading to synthesis of a protein that stabilizes the renin mRNA, thus lengthening its halflife in the cell and boosting synthesis. For more details of the direct action on the renin promoter, see Figure 4.



Figure 2.

Mouse renin genes. a: Molecular arrangement in two‐and one‐gene mice. J and vertical arrow indicate duplication junction. Horizontal arrows show the major transcription‐start site of each gene, as well as direction of transcription. Also shown are DNA insertions: intracisternal A particle (IAP) and mouse insertion‐1 (M1), as well as a heterothyro tropic factor (HFT) island in the 3′‐flanking DNA of each gene. The region indicated by the pentagon immediately upstream of each gene is enlarged in b. b: Enlargement of proximal 5′‐flanking DNA, showing the location of the common insertion relative to the rat and human renin genes, as well as the additional insertions in mouse Ren‐2: 5′, a 143 bp insertion, and, within the common insertion, a type‐2 Alu‐like repeat element. Triangles at ends of boxes refer to direct repeat sequence bordering the insertion site.



Figure 3.

Physiologically relevant functional elements associated with human and mouse renin genes, including far‐upstream enhancer that together with the Pit‐1‐like sequence in proximal promoter DNA is required to achieve normal activity of the renin promoter. A classical silencer element also exists in intron 1. Regulatable expression is mediated via an action of cyclic adenosine monophosphate (cAMP) response element (CRE)–binding protein (CREB) on the CRE (see Fig. 4 for details on the mechanism involved). Part of the cAMP response also involves the Pit‐1‐like site via a CREB‐independent mechanism 124, 462.



Figure 4.

Hypothesis for mechanism by which cyclic adenosine monophosphate (cAMP) mediates physiological control of the human renin gene. Experiments have shown that in renin‐synthesizing cells an increase in cAMP activates protein kinase A (PKA), which in turn phosphorylates cAMP response element‐binding protein (CREB), causing it to bind to the cAMP response element (CRE). This appears to involve a CREB‐activating transcription factor‐1 (ATF‐1) heterodiner or CREB homodimer 124, 462. In unstimulated cells, ATF‐1 is phosphorylated and, by binding to the CRE, may suppress the promoter. The fact that the CRE has low binding affinity coupled with the low phosphorylation of CREB, its ability to undergo rapid deposphorylation, as well as the capacity for greatly enhanced responsiveness of the promoter under conditions that cause CREB‐1 phosphorylation provides a mechanism for establishing a considerable regulatable response range for transcription of the renin gene under various physiological conditions 462. Since PKA and Ca2+/calmodulin‐dependent protein kinases selectively phosphorylate CREB and AFT‐1, possible that a mechanism exists for the convergence and integration of multiple extracellular signals that stimulate (via cAMP) or inhibit (via Ca2+/calmodulin) renin gene expression in renin‐expressing cells in vivo. ℗ is phosphorylation site.



Figure 5.

Renin precursor and processing sites in mouse, rat, and human (not drawn to scale). Initial hydrolysis of the N‐terminal signal (pre) peptide occurs prior to completion of synthesis of the nascent protein (site indicated by small arrow nearer left end of polypeptide chain in each case). Question mark at the rat signal peptide–cleavage site and the range of values for amino acids in rat pre and pro fragments indicate uncertainty as to the actual site of hydrolysis. After completion of synthesis of the precursor (prorenin), activation in vivo is achieved by hydrolysis at the site indicated by the large vertical arrow. (This differs for rat because rat prorenin has a lysine instead of an arginine at the activation site that is used in the other species.) At least a portion of the active renin is later cleaved at the site shown by the small arrow toward the right side of the polypeptide chain, to give active two‐chain renin. The position of this cleavage differs for humans and in humans the two‐chains produced are not held together by disulfide bridges (‐S—S‐), as is the case for mice and rats. Numbers preceded by + indicate amino acid number with respect to the first amino acid of the mature protein, designated +1. Numbers followed by aa indicate the amino acid number in each polypeptide segment.

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Article Title: Renin
 

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Brian J. Morris. Renin. Compr Physiol 2011, Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance: 1-58. First published in print 2000. doi: 10.1002/cphy.cp070301