Inhibition of the renin-angiotensin system in normotensive type 2 diabetes: effects and mechanisms of action

The majority of clinical trials, investigating the effects of angiotensin-receptor antagonists on the diabetic kidney, have focused on hypertensive patients, thereby leaving the possibility that reduction of the systemic blood pressure explains for (most of ) the renoprotective eff ects1-5. Therefore, we studied the effects of the angiotensin-receptor antagonist losartan on urinary albumin excretion, renal function and blood pressure in normotensive patients with type 2 diabetes mellitus and microalbuminuria. The significant reduction in urinary albumin excretion rate by 35%, which we observed after 10 weeks of losartan treatment, is quantitatively comparable to the antiproteinuric effects of losartan in hypertensive diabetic patients1,2,4,6,7. In our normotensive patients, this reduction could not be explained by changes in systemic blood pressure or creatinine clearance, suggesting the involvement of other losartan-mediated mechanisms. First, antagonising the intrarenal angiotensin II leads to favorable intraglomerular haemodynamics, like reduction in arteriolar resistance and intraglomerular pressure, thereby increasing renal plasma flow, reducing the filtration fraction and thus urinary albumin excretion8,9. These changes mainly account for the early rapid component of albuminuria reduction, which parallels the time-course of changes in renal haemodynamics and is thought to be maximal within the first weeks of treatment10,11. Our results of the order of magnitude of the antiproteinuric effect after 5 respectively 10 weeks of losartan treatment, as well as the fact that urinary albumin excretion returned to pretreatment levels in the 5-week placebo washout period, are in concordance with these observations and thus probably result mostly from renal haemodynamic factors. Secondly, losartan treatment probably results in slower, non-haemodynamic renal changes as well, contributing to the well-established long-term renoprotective effects of angiotensin II antagonists in patients with diabetes mellitus3-5. These changes possibly involve improvement of endothelial function and reduction of the chronic low-grade infl ammatory state12,13. However, we have no data on this in our patient population to support this assumption in our studies. Furthermore, the interference of losartan with various growth factor systems is thought to reduce the production of extracellular matrix proteins, finally resulting in slowing down the progression of glomerulosclerosis and tubulointerstitial fi brosis14.