Inhibition of the renin-angiotensin system in normotensive type 2 diabetes: effects and mechanisms of action
Year: 2007
Type: dissertation
Abstract: The majority of clinical trials, investigating the effects of angiotensin-receptor antagonists \\non 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 \\neff ects1-5. Therefore, we studied the effects of the angiotensin-receptor antagonist losartan \\non urinary albumin excretion, renal function and blood pressure in normotensive patients \\nwith type 2 diabetes mellitus and microalbuminuria. The significant reduction in urinary \\nalbumin excretion rate by 35%, which we observed after 10 weeks of losartan treatment, \\nis 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 \\nchanges in systemic blood pressure or creatinine clearance, suggesting the involvement of \\nother losartan-mediated mechanisms. \\n\\nFirst, 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. \\nThese changes mainly account for the early rapid component of albuminuria reduction, \\nwhich parallels the time-course of changes in renal haemodynamics and is thought to be \\nmaximal within the first weeks of treatment10,11. Our results of the order of magnitude of the \\nantiproteinuric effect after 5 respectively 10 weeks of losartan treatment, as well as the fact \\nthat 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 \\nrenal haemodynamic factors. \\n\\nSecondly, losartan treatment probably results in slower, non-haemodynamic renal changes \\nas well, contributing to the well-established long-term renoprotective effects of angiotensin \\nII 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. \\nHowever, we have no data on this in our patient population to support this assumption in \\nour studies. Furthermore, the interference of losartan with various growth factor systems is \\nthought to reduce the production of extracellular matrix proteins, finally resulting in slowing \\ndown the progression of glomerulosclerosis and tubulointerstitial fi brosis14.
Author: Adrienne A.M. Zandbergen
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1698169390