RAAS Cell Connectome

The Renin-Angiotensin-Aldosterone System (RAAS) is a hormone system within the body that regulates blood pressure and fluid balance, and is primarily regulated by the rate of renal blood flow. The RAAS includes many components, organs, cells, and genes, which are systematically connected. Three main hormones are included in the RAAS: renin, angiotensin II and aldosterone. In addition, the RAAS comprises a cascade of enzymes, substrates, and receptors expressed in different cell types in organs throughout the body and interacting in an endocrine fashion. The RAAS plays a crucial role in physiology, regulating sodium and water homeostasis. Furthermore, there are also non-classical aspects of the RAAS system (Ref: Bader, 2010), with components distributed throughout various tissues of the body and having different functionalities.

Inappropriate RAAS activation causes highly lethal consequences in diseases, including congestive heart failure, chronic kidney disease, primary aldosteronism, and most commonly hypertension. The blockers of the RAAS, including renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, play a cornerstone role in the hypertension treatment.

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Above is a RAAS schematic figure, made by Soupvector - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=66583851

RAAS connectome of interactions:

The RAAS connectome consists of a series of interactions that involve different biomolecules at different cell types, tissues, and organs:

• Renin generation: When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor prorenin in the blood into renin
• Renin secretion: Renin is secreted directly into blood circulation.
• Angiotensinogen to angiotensin I by renin: Plasma renin converts angiotensinogen, released by the liver, to angiotensin I.
• Angiotensin I to angiotensin II by ACE: Angiotensin I is subsequently converted to angiotensin II by the angiotensin-converting enzyme (ACE) found on the surface of vascular endothelial cells, predominantly those of the lungs.
• Angiotensin II inducing increased blood pressure:
  • Angiotensin II inducing increased blood pressure as a vasoconstrictive peptide: Angiotensin II, a potent vasoconstrictive peptide, causes blood vessels to narrow, resulting in increased blood pressure.
  • Angiotensin II inducing increased blood pressure through aldosterone: This process includes the following parts:
  • Angiotensin II inducing aldosterone secretion: Aldosterone stimulating the secretion of the hormone aldosterone from the adrenal cortex.
  • Aldosterone inducing sodium reabsorption: Aldosterone causes the renal tubules to increase the reabsorption of sodium.
  • Reabsorbed sodium causing reabsorption of water into blood: Reabsorbed sodium causes the reabsorption of water into the blood
  • Reabsorbed sodium causing excretion of potassium: Reabsorbed sodium causes the excretion of potassium (to maintain electrolyte balance).
  • Excreted potassium increasing extracellular fluid: Excreted potassium increases the volume of extracellular fluid in the body.
  • Increased extracellular fluid causing increased blood pressure: The increased volume of extracellular fluid in the body increases blood pressure.

Cell types in RAAS connectome (from CL)

    RAAS includes the following cell types from different organs:

• Enterocytes, renal proximal tubular cells: located in small intestine, kidney, lung.
• Hepatocytes: located in liver.
• Intraglomerular mesangial cells: located in kidney.
• Juxtaglomerular cells (i.e., Specialized vascular smooth muscle cells): located in kidney.
• Pulmonary vascular endothelial cells: located in lung.
• Renal tubular epithelial cells ("principal cell" subtype): located in kidney.

Locations (from UBERON)

    RAAS cell connectome is located at:

• adrenal
• blood
• brain
• kidney
• lung
• small intestine
• smooth muscle

RAAS Molecular Components

    RAAS includes the following molecular components:

• Amiloride-sensitive epithelial sodium channel (ENaC) (SCNN1A; SCNN1B; SCNN1G): located in kidney. Canonical cell type: Renal tubular epithelial cells ("principal cell" subtype).
• Angiotensin-converting enzyme (ACE): located in lung. Canonical cell type: Pulmonary vascular endothelial cells.
• Angiotensin-converting enzyme-2 (ACE2): located in small intestine, kidney, lung. Canonical cell type: Enterocytes, renal proximal tubular cells
• Angiotensin II receptor, type 1 (AGTR1): located in Heart, vasculature, kidney, brain.
• Angiotensinogen (AGT): located in liver. Canonical cell type: Hepatocytes.
• Mineralocorticoid receptors (NR3C2): located in kidney. Canonical cell type: Renal tubular epithelial cells ("principal cell" subtype).
• Renin (REN): located in the kidney. Canonical cell type: Specialized vascular smooth muscle cells.

Biological Processes (from GO)

• regulation of blood pressure: GO_0008217.
• renin-angiotensin blood pressure control: GO_0001991.
• renin-angiotensin regulation of aldosterone production: GO_0002018 .
• renin-angiotensin regulation of blood vessel size: GO_0002034.
• renin-angiotensin regulation of blood volume: GO_0002016.
• renin secretion into blood stream: GO_0002001.

Biomarkers

• Plasma aldosterone/renin ratio: Plasma aldosterone/renin ratio under standardized conditions (correction of hypokalemia and withdrawal of aldosterone antagonists for 4-6 wks). Reference: Whelton et al., 2017.
• More to add. Stay tuned ...

Gene expression

• Bulk tissue gene expression for AGTR1: https://gtexportal.org/home/gene/AGTR1.
• More to add. Stay tuned ...

Pathways and functional maps

• WikiPathways: Renin-angiotensin-aldosterone system (RAAS) (Homo sapiens): https://www.wikipathways.org/index.php/Pathway:WP4756.
• ACEIs bind ACE: Reactome: R-HSA-9614933.
• More to add. Stay tuned ...

References

• Wiki: https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system.
• Riet LT, van Esch JHM, Roks AJM, van den Meiracker AH, Danser AHJ. Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res. 2015 Mar 13;116(6):960-75. doi: 10.1161/CIRCRESAHA.116.303587. PMID: 25767283.
• Bader M. Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy. Annu Rev Pharmacol Toxicol. 2010. PMID: 20055710.

 

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