New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Abstract

The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

Baseline characteristics in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)

“…28 Animal studies suggest that aliskiren reduces the number of (pro)renin receptors in the kidney. 29 Since non-dipping of night-time blood pressure and enhanced diurnal blood pressure variability are frequently present in patients with CKD and long standing diabetes, [30][31][32] long lasting stable blood pressure reduction as obtained with aliskiren might prove beneficial.…”

AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease

“…Several reports suggest that the beneficial effects of aliskiren are due to a decrease in ANG II production, while others have suggested an additive effect of aliskiren to antagonize the increased plasma renin activity (PRA) due to AT 1 blockade (9). Renin inhibition has been suggested to be superior to ACE inhibition or AT 1 antagonism in previous studies (22).…”

Drug and Diabetic Nephropathy

“…By inhibiting the enzymatic conversion by renin of Angiotensinogen to Angiotensin I, DRIs inhibit the initial and rate-limiting step in the RAAS cascade, thus reducing the product ion of al l downstream products derived from Angiotensin 120,121 . Furthermore, in both clinical studies 122 and in experimental animals 123 , aliskiren reduces plasma and/or urinary excretion of aldosterone. The role of aldosterone in endothelial dysfunction, inflammation, proteinuria and fibrosis is well known 97 .…”

“…First, aliskiren not only inhibits renin but also inhibits the activity of prorenin 124 following its non-proteolytic activation upon binding to the (pro)renin receptor 125 . This may be of particular importance in diabetes in which prorenin levels are elevated and may contribute to local Ang II formation 126 . Second, aliskiren blocks the circulating RAAS and lowers blood pressure 127 .…”