Blockade of the renin-angiotensin and endothelin systems on progressive renal injury

The renin-angiotensin system (RAS) and endothelin system may both play a ro le in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockad e of the RAS with an ACE inhibitor and an angiotensin type 1(ATI) receptor antagonist; second, to examine the relative efficacy of endothelin A recept or antagonism (ETA-RA) compared with combined endothelin A/B receptor antag onism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotal ly nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: peri ndopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), EMS 193884 ( ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either p erindopril or BMS193884, Treatment with irbesartan or perindopril was assoc iated with an improved glomerular filtration rate and reductions in blood p ressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-b eta (1) and matrix protein type IV collagen, The combination of irbesartan with perindopril was associated with further reductions in blood pressure a nd urinary protein excretion. No beneficial effects of either EMS 193884 or bosentan were noted. Furthermore, the addition of EMS 193884 to irbesartan did not confer any additional benefits. These findings suggest that the RA S but not the endothelin system is a major mediator of progressive renal in jury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.