Introduction

Renin is an aspartyl protease released by the juxtaglomerular cells of the kidneys in response to perceived low blood pressure and renal perfusion. It plays an essential role in the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS), responsible for the homeostasis of blood volume and mean arterial blood pressure. Renin also acts as a hormone, binding to pro-renin receptors, causing an increase in the conversion of angiotensinogen to angiotensin I.[1][2]

Fundamentals

Understanding the fundamental physiological mechanisms of renin requires understanding the cells of the juxtaglomerular apparatus, which includes juxtaglomerular (JG) cells, macula densa cells, and the extra-mesangial cells. JG cells are responsible for the exocytosis of renin and have similar structures to smooth muscle; this reflects in their location within the tunica media of glomerular afferent arterioles. Renin is stored in the form of prorenin, and the cleavage of prorenin facilitates its conversion to renin by intracellular microsomes. JG cells are specialized cells characterized by a large nucleus with an increased number of the rough endoplasmic reticulum (RER) and Golgi apparatus, which can be explained by its increased physiological requirement to produce renin. They also have distinct features of gene expression in comparison to other cells of the JGA, allowing it to play an endocrinological and contractile role. Macula densa cells are located in the distal ascending loop of Henle and distal convoluted tubule and detect sodium concentration in the tubular fluid using sodium-potassium-chloride symporters. They are essential in controlling the release of renin, and its mechanism is outlined below. In contrast, the role of extra-mesangial cells is relatively unknown; however, researchers postulate that they play a role in the secretion of erythropoietin.[3][4]

There are three fundamental mechanisms to which triggers the release of renin [5]:

1. Baroreceptor detection of a decrease in renal perfusion pressure.
2. Macula densa detection of a decrease in sodium in the renal tubule triggering the release of vasodilatory compounds such as prostaglandin and nitric oxide to increase glomerular blood flow and trigger renin release, respectively.
3. Beta-1 adrenergic receptor activation via an increase in the activity of the sympathetic system.

Following its release into the bloodstream, renin acts on angiotensinogen, a glycopeptide continuously produced by the liver, forming angiotensin I. In humans, due to angiotensinogen's continuous production, there is an excess of angiotensinogen present in blood plasma, meaning that the conversion to angiotensin I is the rate-limiting step in the sequence of the RAAS. This is explainable by the relationship between the number of substrate molecules and enzyme active sites. As there is a constant abundance of substrates (angiotensinogen) that are available to bind to the active sites of released renin, the rate of reaction, which is mediated by the formation of enzyme-substrate complexes, will be determined by the number of active sites (amount of renin).

Angiotensin I is further cleaved into angiotensin II by the angiotensin-converting enzyme (ACE), located in the endothelium of the lungs and kidneys. Angiotensin II then acts on the nephron to increase the reabsorption of sodium and water through the constriction of afferent glomerular arterioles and increase in activity of the sodium-proton symporter in the proximal convoluted tubule of the kidney. Angiotensin II also triggers the release of aldosterone from the zona glomerulosa of the adrenal cortex as well as antidiuretic hormone (ADH) from the posterior pituitary gland, which both act to increase serum sodium levels and total fluid volume.[5]

Cellular Level

Three intracellular mechanisms affect the expression and release of renin.

1. Cyclic GMP (cGMP) and nitric oxide (NO) - NO is a known vasodilator that also acts on JG cells to increase renin release. As in smooth muscle cells, NO acts via induction of intracellular cGMP formation, which can then inhibit phosphodiesterase. Phosphodiesterase then impairs the breakdown of cAMP, triggering renin release. On the other hand, cGMP can also suppress renin secretion through activation of protein kinase type II. However, it is important to note that current research suggests that cGMP has both inhibitory and stimulatory effects on the release of renin. The degree to which it affects renin release is yet to be understood.[5][6]
2. Calcium ions - Calcium ions also control the release of renin; they are responsible for the negative feedback loop elicited by subsequent products of the RAAS, such as angiotensin II and antidiuretic hormone. These products act to increase the concentration of JG cell calcium levels, which will inhibit the release of renin. This is referred to as the "calcium paradox" as exocytosis of intracellular secretory vesicles is typically stimulated in the presence of raised intracellular calcium. Researchers postulate that this due to the inhibition of adenylate cyclases AC5 and AC6 by calcium.[5][7]
3. Cyclic AMP (cAMP) - cAMP is a key secondary messenger involved in cellular signal transduction involved in the activation of G-protein coupled receptors (GPCRs). GPCR activation triggers the conversion of adenosine triphosphate to cAMP, which then acts on protein kinase A which further phosphorylates essential proteins involved in protein expression such as transcription factors.[5][8]

Molecular Level

Renin is an aspartyl protease. Its gene is located on chromosome 1, containing ten exons and nine introns. The gene is responsible for the expression of 406 amino acids, which include pre and pro segments consisting of 20-23 and 43-47 amino acids, respectively. Renin is initially synthesized from pre-pro-renin. Following the expression of pre-pro-renin from the ribosomes of the RER, cleavage of the pre-segment by lytic enzymes immediately occurs to form pro-renin. Once stimulated, pro-renin then transfers to the Golgi body, where it is cleaved and modified into renin in preparation for exocytosis via secretory vesicles.[5][9]

Testing

Plasma renin levels can be an important diagnostic test in distinguishing those with hypertension caused by hyperaldosteronism. In patients with primary hyperaldosteronism, such as in those with Conn syndrome, renin levels will be low, and aldosterone levels elevated. In contrast, in patients with secondary hyperaldosteronism, such as in congestive heart failure, both renin and aldosterone levels will increase. 

Clinical Significance

Renin is an essential and effective physiological regulator of blood volume; however, it also plays a significant role in the pathogenesis of various conditions. An important condition to note here is hypertension. Through the overactivation and overexpression of renin from JG cells, the body retains too much fluid, causing increased blood volume and blood pressure. For example, in the presence of atherosclerotic renal artery stenosis, the kidneys may falsely perceive a decrease in renal perfusion, inappropriately releasing renin despite the patient having a physiologically normal fluid status, which may lead to accelerated hypertension. Current first-line pharmacological management methods for hypertension in such conditions involve the inhibition of RAAS. Examples include ACE inhibitors and angiotensin II receptor blockers, which act on later steps of the cascade to inhibit the physiological consequences of RAAS overactivation. These drugs are highly effective but also limited in their action due to the inhibition of subsequent reactions following renin release. Although successfully inhibit the conversion of angiotensin I to angiotensin II, ACE inhibitors do not affect renin - this means renin levels will eventually increase in compensation to the effect of these drugs, implying the eventual and inevitable return of hypertension.

These potential adverse effects result from the intermediate inhibition of RAAS, which is resolvable via the use of a newer generation of antihypertensive agents called direct renin inhibitors (DRIs). These play a significant role in managing hypertension by directly blocking the rate-limiting step of the RAAS. By inhibiting renin, it is possible to inhibit all molecules further along the cascade, including the release of angiotensin I, angiotensin II, aldosterone, and ADH. An example is aliskiren, which the FDA approved in 2007 to be used as a monotherapy or in combination with other hypertensives. However, due to the overwhelming lack of evidence and cost-effectiveness compared to ACE inhibitors, it is not a first-line medication.[10][11][12]