The renin-angiotensin system.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in developed countries where type 2 diabetes mellitus has reached epidemic proportions. Although the exact pathogenesis of DN is not fully understood and is likely diverse in nature, there are convincing data that the renin-angiotensin system (RAS) is a major mediator of renal injury. Angiotensin II (Ang II), traditionally playing a central role as a mediator of glomerular hemodynamic adaptation and injury, is now recognized to exert proinflammatory action leading to upregulation of chemokines, adhesion molecules, and other fibrogenic growth factors that culminate in a decline of renal function. Hyperglycemia and mechanical stress deriving from glomerular hypertension are the key factors underlying pathogenesis of DN. The common signaling pathways stimulated by high glucose and mechanical insult may act synergistically, thereby accelerating the cell damage. Podocytes are subjected not only to the load of filtered glucose but also to diverse mechanical forces. Both high glucose and mechanical stress may impair the protein systems anchoring the podocyte foot processes in the glomerular basement membrane, therefore blunting resistance of these cells to mechanical forces in addition to the inflammatory insults. Loss of the podocytes is irreversible due to their inability to proliferate and to replenish damaged cells. Podocytes are injured early in the course of DN, which, most likely, underlies further glomerular and renal damage in diabetes. Under normal physiological conditions, podocytes play a specific role in the maintenance of intraglomerular RAS balance with enzymatic activities that predominantly lead to ANG1-7 and ANG1-9 formation, as well as Ang II degradation. ANG1-7 counteracts the proinflammatory actions of Ang II. These enzymatic activities are altered in a nonphysiological environment such as hyperglycemia that mimics diabetic kidney disease. An understanding of the local intraglomerular RAS will provide a novel approach for early stages of DN.