The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis.

Regardless of the primary cause, progressive renal deterioration with sclerosis is a hallmark of many renal diseases. Several studies have shown the superiority of angiotensin-converting enzyme inhibitors compared with other antihypertensive agents in providing protection from progressive renal deterioration. Furthermore, animal studies have shown that angiotensin II antagonists in excess of antihypertensive doses can also ameliorate or reverse glomerulosclerosis, leading to the hypothesis that angiotensin II has nonhemodynamic effects that mediate the renoprotective effects shown in these investigations. Although historically angiotensin II has been associated with salt and fluid homeostasis, recent data show that angiotensin II induces cell growth and matrix accumulation in glomerular cells. Plasminogen activator inhibitor-1 has been shown to be the major inhibitor of tissue plasminogen activator and urokinase-like plasminogen activator, with potentially important effects not only on thrombosis/fibrinolysis, but also on matrix degradation because of the proteolytic actions of these substances. Angiotensin II has been shown to influence the actions of plasminogen activator inhibitor-1 and, consequently, its thrombotic and sclerotic effects. Various studies, both in vitro and in vivo, have shown that direct hemodynamic actions, modulation of endothelial injury, and growth factor actions also may be important in the development of sclerosis. These factors can be directly modulated by angiotensin II inhibition. Sclerosis may even be reversed when therapies augment matrix degradation processes, both by directly increasing proteolytic activity and by downregulating inhibitors of matrix degradation. These observations indicate that angiotensin II is important in fibrotic as well as thrombotic renal injuries that lead to progressive renal disease and also in the development of therapies such as specific angiotensin receptor antagonists to prevent or reverse these conditions.