Role of Endothelin Receptors for Renal Protection and Survival in Hypertension

Hypertension causes mesangial cell growth and glomerulosclerosis and is an important cause of chronic renal failure.1 Urinary loss of proteins is determined by dysfunction of the glomerular filtration barrier for which intact function of visceral glomerular epithelial cells (podocytes) is critical.2,3 Consequently, microalbuminuria and albuminuria have become reliable and early markers of glomerular disease in hypertensive subjects.1,4 In patients, treatment of hypertension with several types of drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers but also calcium antagonists or β-blockers, delays the development of renal disease,4 and under certain conditions, proteinuria may actually regress.5 Experimental models of hypertensive renal disease show that established proteinuria and glomerulosclerosis may even be reversed by some drugs.6 However, in the majority of these studies, the drugs also had pronounced antihypertensive effects; thus, pressure-lowering effects of the drugs possibly also contributed to glomerular “healing.”7Mimicking activation of the renin–angiotensin–aldosterone system (RAAS) in rats by infusion of angiotensin II results in hypertension and pronounced vascular hypertrophy8,9; renal and vascular endothelin (ET)-1 synthesis also increases, suggesting an interaction between ET and the RAAS.8,9 This link is further strengthened by studies showing that ETA receptor blockade completely normalizes the structural changes in the vasculature induced by angiotensin II, despite only partially reducing blood pressure.9 Even salt-sensitive hypertension induced by angiotensin II seems to depend on the ET system.10The interaction between these systems has been investigated further using a genetic model of RAAS-dependent hypertension, a transgenic rat model carrying the mouse renin 2 gene.11 This model of renin-dependent hypertension is characterized by malignant hypertension, and untreated animals die prematurely because of myocardial infarction, heart failure, and stroke.11 Previous studies have investigated the effects of ET blockade on hypertension and target organ injury …