ANGIOTENSIN II-MEDIATED RENAL INJURY

During the past decade, experimental and clinical evidence has indicat ed an important role for the renin-angiotensin system in the progressi ve destruction of nephrons in a wide variety of chronic renal diseases . Studies have indicated that in the subtotally nephrectomized rat mod el of progressive glomerulosclerosis, in experimental diabetes mellitu s, in the chronic phase of puromycin aminonucleoside-induced nephrotic syndrome and in Heymann's nephritis, angiotensin-converting enzyme (A CE) inhibitors dramatically preserve both nephron structure and functi on. Clinical studies have similarly noted that chronic administration of ACE inhibitors inhibits progression of renal failure in type I diab etes and type II diabetes as well as primary glomerulopathies, sickle cell nephropathy, systemic lupus erythematosis, chronic pyelonephritis and adult polycystic kidney disease. Current evidence suggests that t he beneficial effect of ACE inhibitors is primarily due to inhibition of angiotensin II production, and there is strong suggestive evidence for increases in local intrarenal activation of the renin-angiotensin system in these conditions. In obstructive uropathy, activation of the renin-angiotensin system has also been shown to be an important aspec t of the early functional changes and may be of importance in the subs equent generation of interstitial fibrosis. In the obstructed kidney, renin and angiotensinogen production increase and type I angiotensin r eceptors decrease. Inhibitors of angiotensin II production and angiote nsin II action partially reverse the vasoconstriction and the reduced renal blood flow, and abolish the changes in expression of AT(1) mRNA induced by obstruction. Studies suggest that the angiotensin-mediated increases in tubulointerstitial fibrosis may be mediated by increased production of transforming growth factor-beta. In summary, the existin g evidence convincingly indicates that angiotensin II plays a major ro le in the mediation of progressive glomerular and tubulointerstitial i njury, and that increased angiotensin II in these conditions is a resu lt of activation of local. intrarenal renin-angiotensin systems.