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 blood volume homeostasis 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 juxtaglomerular apparatus's cells, including juxtaglomerular cells, macula densa cells, and extra-mesangial cells. Juxtaglomerular cells are responsible for the exocytosis of renin and have similar structures to smooth muscle; this is reflected in their location within the tunica media of glomerular afferent arterioles. Renin is stored in prorenin, and the cleavage of prorenin facilitates its conversion to renin by intracellular microsomes. Juxtaglomerular cells are specialized cells characterized by a large nucleus with an increased number of the rough endoplasmic reticulum 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 them to play an endocrinological and contractile role. Macula densa cells are located in the distal ascending loop of Henle and distal convoluted tubule, and sodium concentration in the tubular fluid is detected 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 erythropoietin secretion.[3][4]

Three fundamental mechanisms trigger the release of renin:

1. Baroreceptor detection of a decrease in renal perfusion pressure.
2. Macula densa detection of a decrease in sodium in the renal tubule triggers 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 sympathetic system's activity.[5] 

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,  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 sodium and water reabsorption through the constriction of afferent glomerular arterioles and increase the 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 and antidiuretic hormone (ADH) from the posterior pituitary gland, which both 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 - nitric oxide is a known vasodilator that acts on juxtaglomerular cells to increase renin release. As in smooth muscle cells, nitric oxide 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 the 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 increase the concentration of juxtaglomerular cell calcium levels, inhibiting the release of renin. This is called the "calcium paradox," which is the exocytosis of intracellular secretory vesicles typically stimulated by raised intracellular calcium. Researchers postulate that this is due to calcium's inhibition of adenylate cyclases AC5 and AC6.[5][7]
3. Cyclic AMP (cAMP) - cAMP is a key secondary messenger involved in cellular signal transduction in activating 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 on chromosome 1, containing 10 exons and 9 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 pre-pro-renin expression from the ribosomes of the rough endoplasmic reticulum, cleavage of the pre-segment by lytic enzymes immediately occurs to form pro-renin. Once stimulated, pro-renin 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 for distinguishing those with hypertension caused by hyperaldosteronism. In patients with primary hyperaldosteronism, such as those with Conn syndrome, renin levels are low, and aldosterone levels are elevated. In contrast, in patients with secondary hyperaldosteronism, such as those with congestive heart failure, both renin and aldosterone levels 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. The body retains too much fluid through the overactivation and overexpression of renin from juxtaglomerular cells, 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 cascade steps to inhibit the physiological consequences of RAAS overactivation. These drugs are highly effective but also limited in their action due to inhibiting subsequent reactions following renin release. Although they successfully inhibit the conversion of angiotensin I to angiotensin II, ACE inhibitors do not affect renin - this means renin levels 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 using a newer generation of antihypertensive agents called direct renin inhibitors. 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 as a monotherapy or combined 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]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002 Jun;109(11):1417-27. [PMC free article: PMC150992] [PubMed: 12045255]

2.

Scott BB, McGeehan GM, Harrison RK. Development of inhibitors of the aspartyl protease renin for the treatment of hypertension. Curr Protein Pept Sci. 2006 Jun;7(3):241-54. [PubMed: 16787263]

3.

Persson PB. Renin: origin, secretion and synthesis. J Physiol. 2003 Nov 01;552(Pt 3):667-71. [PMC free article: PMC2343457] [PubMed: 12949225]

4.

Fountain JH, Kaur J, Lappin SL. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Mar 12, 2023. Physiology, Renin Angiotensin System. [PubMed: 29261862]

5.

Sparks MA, Crowley SD, Gurley SB, Mirotsou M, Coffman TM. Classical Renin-Angiotensin system in kidney physiology. Compr Physiol. 2014 Jul;4(3):1201-28. [PMC free article: PMC4137912] [PubMed: 24944035]

6.

Wagner C, Pfeifer A, Ruth P, Hofmann F, Kurtz A. Role of cGMP-kinase II in the control of renin secretion and renin expression. J Clin Invest. 1998 Oct 15;102(8):1576-82. [PMC free article: PMC509008] [PubMed: 9788971]

7.

Grünberger C, Obermayer B, Klar J, Kurtz A, Schweda F. The calcium paradoxon of renin release: calcium suppresses renin exocytosis by inhibition of calcium-dependent adenylate cyclases AC5 and AC6. Circ Res. 2006 Nov 24;99(11):1197-206. [PubMed: 17068292]

8.

Wright PT, Schobesberger S, Gorelik J. Studying GPCR/cAMP pharmacology from the perspective of cellular structure. Front Pharmacol. 2015;6:148. [PMC free article: PMC4505077] [PubMed: 26236239]

9.

Zivná M, Hůlková H, Matignon M, Hodanová K, Vylet'al P, Kalbácová M, Baresová V, Sikora J, Blazková H, Zivný J, Ivánek R, Stránecký V, Sovová J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gübler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009 Aug;85(2):204-13. [PMC free article: PMC2725269] [PubMed: 19664745]

10.

Jacobs TF, Salisbury BH, Terrell JM. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 12, 2024. Aliskiren (Archived) [PubMed: 29939645]

11.

Wal P, Wal A, Rai AK, Dixit A. Aliskiren: An orally active renin inhibitor. J Pharm Bioallied Sci. 2011 Apr;3(2):189-93. [PMC free article: PMC3103912] [PubMed: 21687346]

12.

Sen S, Sabırlı S, Ozyiğit T, Uresin Y. Aliskiren: review of efficacy and safety data with focus on past and recent clinical trials. Ther Adv Chronic Dis. 2013 Sep;4(5):232-41. [PMC free article: PMC3752183] [PubMed: 23997927]

Disclosure: Kentaro Trerattanavong declares no relevant financial relationships with ineligible companies.

Disclosure: Jiatong (Steven) Chen declares no relevant financial relationships with ineligible companies.