Kidney Biology

Signaling pathways relevant to kidney biology and function, like the renin-angiotensin-aldosterone system (RAAS), regulate blood pressure, fluid balance, and vascular resistance. RAAS signaling controls key kidney functions, and its dysregulation can lead to conditions like hypertension and chronic kidney disease.

Key Questions About Kidney Biology-Related Signaling Pathways

Learn how the renin-angiotensin system and aldosterone signaling are tightly interconnected, forming the renin-angiotensin-aldosterone system (RAAS), which plays a crucial role in regulating blood pressure, fluid balance and systemic vascular resistance.
What are the key components and interactions in the renin-angiotensin-aldosterone system?

The renin-angiotensin-aldosterone system (RAAS) comprises renin, angiotensin II (ANG II) and aldosterone. These compounds interact through a sequence of biochemical events (1).

Renin is an aspartyl protease that triggers the first step in the RAAS activation. It is primarily secreted into the bloodstream by the kidneys in response to reduced blood pressure. Renin specifically acts on the substrate angiotensinogen, cleaving it into the decapeptide angiotensin I (ANG I). Angiotensin-converting enzyme (ACE) then converts ANG I into the octapeptide ANG II (2).

ANG II is a vasoactive peptide primarily responsible for fluid and electrolyte levels, aldosterone production and other physiological functions. It exerts its actions through G-protein coupled receptors, ANG II Type 1 Receptor (AT1-R) and ANG II Type 2 Receptor (AT2-R) (1).

Aldosterone acts on the kidneys to maintain electrolyte and fluid homeostasis by binding to the mineralocorticoid receptor (MR) on the principal cell of the kidney collecting duct.

The RAAS regulates blood pressure, fluid and electrolyte balance, vasoconstriction, cardiac output, cell growth, angiogenesis and vascular integrity, among other physiological functions. Dysregulation of the RAAS has been implicated in the pathophysiological events associated with hypertension, cardiovascular diseases and kidney diseases (3). 

What is renin-angiotensin signaling

Renin-angiotensin signaling involves a hormone cascade initiated by the release of renin. Renin converts angiotensinogen, produced by the liver, into angiotensin I, which is then converted into angiotensin II by the ACE. ANG II acts on tissues, including the kidneys, heart and brain, to regulate blood pressure, fluid balance and electrolyte levels. ANG II acts on the kidneys by stimulating aldosterone release, which then promotes sodium retention and potassium excretion and increases blood pressure. These actions help maintain renal blood flow and glomerular filtration rate (GFR), the rate at which the kidneys filter waste and excess water from the blood, for normal kidney function (4).

How does renin-angiotensin signaling contribute to blood pressure regulation?

Renin-angiotensin signaling regulates blood pressure primarily through the effects of ANG II. ANG II contributes to blood pressure regulation through vasoconstriction, contracting the vascular smooth muscle in the arterioles, the primary resistance vessels that control blood pressure and flow. It also stimulates aldosterone secretion, increases sodium reabsorption, increases thirst drive within the hypothalamus, stimulates the sympathetic nervous system, stimulates vasopressin release from the hypothalamus and regulates metabolic rate, all contributing to blood pressure regulation (1). 

How does dysregulation of renin-angiotensin signaling impact kidney health?

Dysregulation of renin-angiotensin signaling can lead to conditions such as hypertension, chronic kidney disease (CKD) and heart failure (1). Overactivation of this pathway can cause excessive vasoconstriction and inflammation, which in turn promotes hypertension, kidney fibrosis and eventual kidney damage. The first line of treatment to control blood pressure and protect kidney health in patients with chronic kidney disease is medications that target the renin-angiotensin-aldosterone system. These medications include direct renin inhibitors, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (5).

What therapeutic interventions target the renin-angiotensin system?

Therapeutic interventions targeting the renin-angiotensin system include direct renin inhibitors, angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRA) and aldosterone synthase blocker. They work by reducing vasoconstriction, inflammation, hypertrophy and fibrosis and improving renal perfusion, all of which slow the progression of cardiac and kidney diseases. Hence, these medications are widely used for treating hypertension, heart failure and kidney diseases (6).

New drugs are being developed to improve the treatment of kidney and cardiovascular diseases and patient outcomes. Recently, new components of the RAAS with protective effects, called alternative RAAS pathways, have been identified. The primary peptide in the alternative pathway is Ang 1–7, which is associated with the Mas receptor. As a result of these findings, researchers are now focusing on drugs that activate these alternative pathways (7, 8).

What is aldosterone signaling and how is it important in kidney function?

Aldosterone, a mineralocorticoid hormone, plays a crucial role in regulating fluid and electrolyte balance in the body. The cortical collecting duct in the kidney is the primary location where aldosterone acts (9). It exerts its effects by binding to mineralocorticoid receptors, which then trigger the transcription of target genes, including the epithelial sodium channel (ENaC),  serum/glucocorticoid-regulated kinase 1 (SGK1) and the Na/K-ATPase (Na/K pump), which then induce actions that regulate water and electrolyte balance.

Aldosterone influences kidney function by stimulating increased sodium reabsorption, water retention, potassium excretion, acid (H+) excretion, bicarbonate (HCO3-) excretion and chloride reabsorption (10).

How does aldosterone signaling regulate blood pressure?

Aldosterone regulates blood pressure by inducing ENaC, SGK1 and Na/K-ATPase transcription which then contribute to processes that affect blood pressure including sodium and water reabsorption, potassium excretion and acid-base balance. The kidneys and heart are the main organs that aldosterone acts on to regulate blood pressure (11, 9).

How does dysregulation of aldosterone signaling affect kidney function?

Dysregulation of aldosterone signaling can disrupt kidney health primarily because aldosterone is critical to regulating blood pressure. Impaired aldosterone signaling can cause hyperaldosteronism, where the adrenal glands produce excess aldosterone, leading to hypokalemia, hypertension and chronic kidney disease. On the other hand, inadequate aldosterone production can result in Addison's disease, causing hypotension, high potassium levels and dehydration. Both conditions disrupt electrolyte balance, potentially leading to kidney dysfunction (11). 

References and further reading

  1. Fountain JH, Kaur J, Lappin SL. Physiology, Renin Angiotensin System. [Updated 2023 Mar 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan
  2. Hassani B, Attar Z, Firouzabadi N. The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies. Cancer Cell Int. 2023;23(1):254. Published 2023 Oct 27.
  3. Forrester SJ, Booz GW, Sigmund CD, et al. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev. 2018;98(3):1627-1738.
  4. Kaufman DP, Basit H, Knohl SJ. Physiology, Glomerular Filtration Rate. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan
  5. Alshahrani S. Renin-angiotensin-aldosterone pathway modulators in chronic kidney disease: A comparative review. Front Pharmacol. 2023;14:1101068. Published 2023 Feb 13.
  6. Sparks MA, Crowley SD, Gurley SB, Mirotsou M, Coffman TM. Classical Renin-Angiotensin system in kidney physiology. Compr Physiol. 2014;4(3):1201-1228.
  7. IntechOpen https://www.intechopen.com/chapters/72192 Accessed July 25th, 2024
  8. Martyniak A, Tomasik PJ. A New Perspective on the Renin-Angiotensin System. Diagnostics (Basel). 2022;13(1):16. Published 2022 Dec 21.
  9. IntechOpen https://www.intechopen.com/chapters/67786 Accessed July 25th, 2024
  10. Scott JH, Menouar MA, Dunn RJ. Physiology, Aldosterone. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
  11. Tsilosani A, Gao C, Zhang W. Aldosterone-Regulated Sodium Transport and Blood Pressure. Front Physiol. 2022;13:770375. Published 2022 Feb 7.