What Is Renin-Angiotensin-Aldosterone System (RAAS)?
The renin-angiotensin-aldosterone system is a complex that includes enzymes, proteins, and hormones that aid in regulating blood pressure and volume for the long term. The system affects several organs, including kidneys, glands, and tissues.
The RAAS system regulates blood pressure by increasing sodium reabsorption, water reabsorption, and vascular tone (regulates tissue perfusion). Three main constituents of the RAAS system include the renin enzyme, Angiotensin hormone, and Aldosterone hormone.
How Does the RAAS System Regulate Blood Pressure?
Kidneys have a vital role in the RAAS system. The enzyme renin gets released into the bloodstream when the blood pressure falls. Renin is secreted by kidneys, which are beneficial in regulating blood pressure. Renin acts on a protein called Angiotensinogen produced by the liver. Angiotensinogen gets converted into inactive Angiotensin I. Angiotensin-converting enzyme (ACE) found in various tissues, including the lungs, converts angiotensin I to active angiotensin II.
Angiotensin II is a vasoconstrictor that elevates blood pressure by constricting blood vessels. The hormone stimulates the release of aldosterone from the adrenal glands and antidiuretic hormone from the pituitary gland. Aldosterone and antidiuretic hormone regulate sodium and water reabsorption and potassium excretion through urine. Therefore increasing blood pressure and volume. Other hormones like steroids, estrogen, and thyroid stimulate the RAAS system. The RAAS system is crucial for regulating blood pressure.
Why Is the RAAS System Important for Kidneys?
The RAAS system in healthy individuals helps regulate renal vasomotor activity, maintains salt and water homeostasis, and controls tissue growth within the kidney. However, pathological renal disorders can develop from the overactivity of the cascade. The RAAS system could cause systemic and glomerular capillary hypertension, injuring the glomerulus endothelium. Kidney damage can occur due to proinflammatory and profibrotic effects from angiotensin II and aldosterone. The effects of angiotensin II are related to its binding with the angiotensin II type 1 receptor.
Activation of angiotensin type 1 receptor in the kidney causes hypertension due to sodium retention. The action of angiotensin II on renal hemodynamics is critical for increasing blood pressure. When the efferent arteriole is constricted by angiotensin II, it reduces renal blood flow and increases the glomerular filtration rate by raising glomerular capillary pressure. Angiotensin could also have a direct action on the kidneys. It directly acts on sodium and potassium pumps to enhance sodium reabsorption.
Apart from these, angiotensin II promotes the production of nephrotoxic reactive oxygen species and initiates cell proliferation and tissue modeling by enhancing the production of cytokines and growth factors. Collagen deposition also increases due to the inhibition of proteases. Therefore, it results in glomerulosclerosis (hardening of glomeruli within the kidney) or tubulointerstitial necrosis (death of tubular epithelial cells).
What Is the Role of the RAAS System in Developing and Progressing Kidney Disease?
1. Proteinuria
Activation of the RAAS system can exacerbate proteinuria (protein in urine). Hypertension in the glomerular capillary can enhance their permeability, leading to excess protein filtration. Proteinuria can also occur due to the effects of the RAAS system on nephrin expression. Nephrin is a transmembrane protein in the glomerular podocyte (cells in Bowman’s capsule).
The protein helps maintain the slit integrity of the diaphragm and prevents protein loss from the glomerulus. Proteinuria is a marker for renal disease and induces kidney damage. The presence of protein in urine is considered toxic for renal tubules, causing tubulointerstitial nephritis (inflammation of renal tubules and surrounding tissue) and scarring. Reduction of proteinuria can help maintain renal health.
2. Chronic Kidney Disease
The predominant part of the RAAS system is to regulate blood pressure. The RAAS system regulates the fluids and electrolyte homeostasis by influencing blood vessels, the heart, and the kidneys. Angiotensin II is the main effector within the RAAS system that exerts vasoconstriction on the postglomerular arterioles, increasing glomerular arterioles pressure. Therefore, increasing glomerular hydraulic pressure and ultrafiltration of plasma proteins contribute to the development of chronic kidney disease. Angiotensin II can accelerate renal disease progression by stimulating cell growth and increasing reactive oxygen species production, inflammation, and fibrosis. The aldosterone released can amplify the actions of angiotensin II and contribute to endothelial dysfunction. The size and stiffness of endothelial cells are increased, enabling protein leakage. Higher levels of proteinuria are associated with adverse renal outcomes.
3. Renovascular Hypertension
The RAAS system is vital in regulating hypertension induced by renal artery stenosis (narrowing artery carrying blood to the kidney). Severe stenosis could cause secondary hypertension and kidney damage. Individuals with renal artery stenosis could progress to end-stage renal disease within three to four years. Renal perfusion decreases in the stenosed kidneys, stimulating the renin enzyme within the RAAS system. Therefore, it causes a series of events, initiated by renin release followed by angiotensin II secretion, reduced sodium excretion, and increased sympathetic tone, contributing to the development of renovascular hypertension. In individuals with renal artery stenosis, there is an increase in superoxide production and a significant reduction in glomerular filtration rate (GFR). In individuals with renovascular hypertension, renin release is mediated by prostaglandins. Renal artery stenosis is common in diabetic and elderly patients, causing renal failure.
What Measures Can Be Taken for Renal Protection From the RAAS System?
Drugs that act against the RAAS system and inhibit the release of hormones and enzymes can help slow or halt the disease's progression. Hypertensive drugs like ACE inhibitors and angiotensin receptor blockers (ARB) can effectively reduce hypertension and targeted organ damage. ACE inhibitors prevent renal failure in most patients with diabetic and non-diabetic nephropathy. However, healthcare providers underutilize ACE inhibitors due to the fear of developing hyperkalemia (elevated potassium levels).
Renin inhibitors like Aliskerin can potentially treat high blood pressure associated with chronic kidney disease or renovascular hypertension. ACE inhibitors can be combined with angiotensin II antagonists to maximize RAAS inhibition. Therefore, it reduces proteinuria and GFR decline in diabetic and nondiabetic renal disease patients. Additional treatment with aldosterone antagonists can further enhance renoprotection but can increase the risk for hyperkalemia.
These drugs must be started with a low dose and later enhanced to optimal doses to control blood pressure and proteinuria. The patients must be monitored for kidney failure or hyperkalemia.
Conclusion
Any pathological changes to the RAAS system cascade could contribute to the development of renal dysfunction. The hemodynamic changes with proinflammatory and profibrotic effects induced by angiotensin II and aldosterone could contribute to the development of renal disorders. Therefore, therapies are directed at various components of the RAAS system to slow or halt the progression of end-stage renal damage.
