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The classical view of the RAS is a linear signaling pathway beginning with the conversion of angiotensinogen to ANG I by renin, an enzyme secreted by the kidney. ANG I is converted to ANG II by angiotensin converting enzyme (ACE) ANG II binds to the G-protein coupled angiotensin II receptor type 1. The RAS is a circulating system but we now know that the RAS is also locally expressed in a number of tissues, including the kidneys and the heart. ANG II exerts adverse hemodynamic and non-hemodynamic effects on renal cells. The hemodynamic effects include: systemic vasoconstriction and increases in glomerular capillary pressur. The non-hemodynamic effects include: stimulation of proximal sodium re-absorption, stimulation of gluconeogenesis and ammoniagenesis, growth factor release, stimulation of extracellular matrix production, inflammatory cytokine release, and monocyte/macrophage migration. ANG II also induces epithelial-mesenchymal transition. ANG II can also be processed by enzymes with important implications for kidney injury. The recent discovery and characterization of a homolog for ACE, ACE2, builds on this emerging theme of complexity. ACE2 expression is highest in the heart, kidney, and the vascular endothelium. ACE2 differs importantly from that of ACE. ACE hydrolyzes ANG I to ANG II while ACE2 hydrolyzes ANG II to ANG 1–7. Accordingly, ACE2 is predicted to reduce tissue ANG II and increase ANG 1–7. I will describe our work treatment with ACE2 in an experimental model of proteinuric kidney disease which we think will shift the paradigm for management of proteinuria in glomerular diseases which currently emphasizes RAS blockade.