Role of the Intrarenal Renin-Angiotensin-Aldosterone System in Chronic Kidney Disease

Abstract

The existence of local or tissue-based renin-angiotensin-aldosterone systems (RAAS) is well documented and has been implicated as a key player in the pathogenesis of cardiovascular and renal diseases. The kidney contains all elements of the RAAS, and intrarenal formation of angiotensin II not only controls glomerular hemodynamics and tubule sodium transport, but also activates a number of inflammatory and fibrotic pathways. Experimental and clinical studies have shown that the intrarenal RAAS is activated early in diabetic nephropathy, the leading cause of chronic kidney disease (CKD). Although angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the rate of decline in kidney function in patients with diabetic and non-diabetic nephropathy, many patients still progress to end-stage renal disease or die from cardiovascular events. There is still a clear need for additional strategies to block the RAAS more effectively to reduce progression of CKD. The focus of this paper is to review the importance of the intrarenal RAAS in CKD and recent findings in renin-angiotensin biology pertinent to the kidney. We also discuss additional strategies to inhibit the RAAS more effectively and the potential impact of direct renin inhibition on the prevention and management of CKD.

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

“…The kidney contains all the necessary components for local RAAS activation and indeed renal tissue concentrations of angiotensin II (Ang II) are reported to be significantly higher than plasma concentrations. 118,119 As such, quantification of plasma components of RAAS does not necessarily translate to the degree of activation of RAAS within the kidney. 120 RAAS is particularly important as a modulator of blood pressure and fluid balance through alteration in sodium and water homeostasis as well as being integral to intrarenal haemodynamics and glomerular filtration.…”

“…Ang II mediates its effects predominantly via the type 1 (AT1) receptor which has a wide distribution throughout the kidney although type 2 receptors (AT2) are present albeit with a more limited distribution. 118 However, it is now recognized that a number of further products of both Ang I and Ang II may play important regulatory roles (e.g. Ang (1-7)/Mas and Ang IV/AT4 pathways) and may have impact in the pathogenesis of CKD (Figure 4).…”

“…Ang (1-7)/Mas and Ang IV/AT4 pathways) and may have impact in the pathogenesis of CKD (Figure 4). 118,121,122 Ang II in particular has been highlighted as an important mediator in the progression of CKD. It acts as a potent vasoconstrictor contributing to the development of glomerular hypertension and hyperfiltration and that it may modulate the permeability of the glomerular filtration barrier at least partly by altering podocyte interactions.…”

Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II

“…In support of this notion, studies have shown that renal AII is elevated in hypertension and kidney diseases in parallel to their severity. 4,5 Renal AII is also increased in animal models of glomerular diseases, including adriamycin and puromycin aminonucleoside nephropathies, 6 albumin overload, 7,8 and immune complex nephritis. 9 Several mechanisms have been proposed to explain the local upregulation of AII in glomerular diseases, including local increase of renin, [10][11][12][13] angiotensin I converting enzyme (ACE), [7][8][9]14 or angiotensinogen (Agt), 7,8,15,16 activation of prorenin by prorenin receptor, 17 type 1 AII receptor-mediated uptake and endosomal accumulation of AII, 18 generation of AII through alternative enzyme pathway, 19,20 and decrease in ACE2.…”

Extracellular Volume and Glomerular Filtration Rate in Children with Chronic Kidney Disease

“…ECV is tightly controlled as a critical function of the kidney. However, kidney dysfunction and disease are associated with activation of the renin-angiotensin aldosterone system, the importance of which in the regulation of blood pressure (BP) and fluid balance has long been recognized (1). Renin-angiotensin aldosterone system activation and an accompanying positive sodium balance may lead to expanded ECV and hypertension (2).…”