Renin

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Introduction

Renin is an important central hormone that controls blood pressure and various other physiological functions. Renin was discovered more than 100 years ago, but only recently has the origin of renin and the mechanisms of renin synthesis and secretion been better understood. The main source of renin is the juxtaglomerular cells (JGCs), the renin-angiotensin system (RAS) is present in JGCs, in addition to local RASs in various other tissues. JGCs originate in situ within the mesenchymal cells unrelated to the smooth muscle lineage within the metanephric kidney. Free intracellular Ca²⁺ inhibits renin secretion in JGCs, whereas cAMP stimulates renin release. Recent studies have reported that the effect of cGMP on renin release from JGCs ultimately involves the degradation of cAMP, which is regulated by cGMP. Furthermore, it has been found that renin production is regulated by enhancing or attenuating renin transcription, and the stability of renin mRNA is also regulated by various proteins in renin-producing cells.

The origin of renin-producing cells

The juxtaglomerular cells (JGCs) are the most important source of circulating renin. Because adult mammal JGCs contain myofilaments, JGCs are generally considered to be metaplastically modified smooth muscle cells. A recent study confirmed the lineage of JGCs using single-cell PCR and double immunostaining combined with lineage. Sequeria Lopez et al. showed that at least two distinct cell populations express either renin or smooth muscle markers, but never both. From E12 to E15, renin cells do not yet express smooth muscle or endothelial markers. Subsequently, a subpopulation of renin-expressing cells significantly exhibited the ability to express smooth muscle markers. Therefore, renin cells are not derived from smooth muscle cells but give rise to them (Fig. 1). Also, smooth muscle cells derived from renin precursors appear to be able to undergo metaplasia to renin cells when needed.

In addition to circulating RAS, there are also local ones, which are present in various tissues such as the heart, brain, and adrenal glands. Although all components of RAS are expressed in these tissues, their mode of action may be quite different. The truncated form of prorenin appears to be the only prorenin that can be imported into the mitochondria. The classical mRNA encoding prorenin does not respond to stimulation of cardiac RAS. Cardiomyocytes can also internalize circulating renin, and there are two possible mechanisms by which this may occur, one by mannose-6-phosphate receptor-mediated endocytosis, which may be a RAS inactivation. The other is the internalization of nonglycosylated prorenin, a mechanism that may be critical for intracardiac RAS and its various functions.

Figure 1. The lineage of the JGC (Persson, P.B. 2003)

Control of renin synthesis

Transcriptional control depends on DNA located upstream of the gene itself. Transcription of renin RNA requires the binding of RNA polymerase II to the essential promoter region of the gene. For the renin gene, there are additional regulatory elements that are responsible for activating or repressing transcription. These regulatory elements are present in areas where significant interspecies homology may occur.

One of the homologous sequences was referred to as a "renin enhancer" when it was studied. In the renin enhancer, cAMP response elements have been identified. To exert a specific effect, transcription factors binding at the enhancer regions must interact with other transcription factors that function in closer proximity to the transcription site, such as proximal promoter elements. Notably, vitamin D₃ and its receptors appear to play an important role in this complex regulatory process. The interspecies homology found in the other two upstream regions of this enhancer sequence suggests the potential existence of many more regulatory sites, but their functional importance remains to be investigated.

Figure 2. Immunolabelling of renin protein in a JGC using rabbit anti-mouse renin antibody (Persson, P.B. 2003)