Several studies have consistently indicated a close association between altered glomerular permeability to proteins and renal damage. Dietary and pharmacologic manipulations that restore the selectivity of the glomerular barrier to macromolecules stop progressive renal injury. We propose that abnormal traffic of proteins through the glomerular capillary has an intrinsic renal toxicity because of protein over-reabsorption by proximal tubular cells. Protein overload induces functional alterations of tubular cells, including overexpression of vasoactive and proinflammatory mediators such as endothelin-1. This review examines the role of endothelin-1 as a trigger of renal damage, both in vitro and in vivo, and summarizes relevant supporting data.