Antifibrotic Roles of RAAS Blockers: Update

Abstract

The rennin-angiotensin-aldosterone system (RAAS) has been well documented in regulating blood pressure, fluid volume, and sodium balance. Overactivity of RAAS promotes both systemic and regional glomerular capillary hypertension, which could induce hemodynamic injury to the glomerulus, leading to kidney damage and renal fibrosis via profibrotic and proinflammatory pathway. Therefore, the use of RAAS inhibitors (i.e., ACEIs, ARBs, and MRAs) as the optional therapy has been demonstrated to prevent proteinuria, and kidney fibrosis and slow the decline of renal function effectively in the process of kidney disease during the last few decades. Recently, several new components of the RAAS have been discovered, including ACE2 and the corresponding ACE2/Ang (1-7)/Mas axis, which are also present in the kidney. Besides the classic RAAS inhibitors target the angiotensin-AT1-aldosterone axis, with the expanding knowledge about RAAS, a number of potential therapeutic targets in this system is emerging. Newer agents that are more specific are being developed. The present chapter outlines the insights of the RAAS agents (classic RAAS antagonists/the new RAAS drugs), and discusses its clinical application in the combat of renal fibrosis.

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“…The rennin‐angiotensin‐aldosterone system (RAAS) has been well documented and reported for the regulation of blood pressure, fluid volume, and sodium balance (Zhang et al, 2019). Therefore, over activity of RAAS has been reported to promote both systemic and regional glomerular capillary hypertension leading to renal damage, vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis via proinflammatory pathways (Gromotowicz‐Poplawska et al, 2016; Zhang et al, 2019).…”

“…The rennin‐angiotensin‐aldosterone system (RAAS) has been well documented and reported for the regulation of blood pressure, fluid volume, and sodium balance (Zhang et al, 2019). Therefore, over activity of RAAS has been reported to promote both systemic and regional glomerular capillary hypertension leading to renal damage, vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis via proinflammatory pathways (Gromotowicz‐Poplawska et al, 2016; Zhang et al, 2019). Angiotensin‐converting enzyme (ACE) inhibitors prevent the formation of more physiologically active angiotensin II from its precursor angiotensin I, and are, therefore, effective for the management of hypertension due to excessive generalized vasoconstriction in the cardiovascular system (Bhandari & Chadburn, 2019; Podzolkov & Tarzimanova, 2018).…”

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“…Non-specific therapies for CKD can slow and even halt progressive loss of kidney function. These include diet and medications for blood pressure control (target <130/80) ( Faqah and Jafar, 2011 ), antifibrotic therapies (inhibitors of renin, angiotensin II, and aldosterone, the latter being a potent profibrotic molecule) ( Zhang et al, 2019 ), and dietary sodium restriction and thiazide diuretics (the latter potentiates the antiproteinuric effects of the renin-angiotensin-aldosterone system antagonists) ( Park et al, 2014 ). SGLT2 inhibitors reduce progression of kidney damage in diabetes ( Tuttle et al, 2021 ) and recently this effect has been shown in non-diabetic kidney disease as well, possibly by reducing proximal tubule stress ( Almaimani et al, 2021 ).…”

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“…ACE-2 cleaves Ang II to Ang (1–7) and exerts vasodilatation, anti-inflammation, and anti-fibrotic effects by Mas receptor system activation. RAAS activation effects depend on the tissue ACE/ACE2 balance, which could be affected by several factors [ 44 , 45 , 46 ].…”