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.

Fig. 1

Multiple roles of the RAAS in the pathogenesis of chronic kidney disease. ECM = Extracellular matrix; NF-κB = nuclear factor-κB; TGF-β = transforming growth factor β.

Fig. 2

Effects of angiotensin receptor blockers on chronic kidney disease progression in patients with type 2 diabetic nephropathy. a Estimated decline in glomerular filtration rate (GFR) in patients receiving placebo or treatment with losartan (Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan [RENAAL]) or irbesartan (Irbesartan in Diabetic Nephropathy Trial [IDNT]). Broken lines represent the range of normal decline in GFR due to aging [49]. b Proportion of patients progressing to end-stage renal disease. c Mortality rates [data from 44, 45].