Glomerulosclerosis and tubulointerstitial damage are characteristics of progressive renal diseases associated with chronic proteinuria. Since numerous studies have demonstrated a correlation between proteinuria and the degree of renal damage, a causal role for proteinuria in the development of progressive renal failure has been postulated. Some in vitro data suggest that endothelins (ET), a family of endogenous peptides, could be involved in the genesis and progression of glomerular damage. Moreover, evidence that tubular cells exposed to high molecular weight proteins are induced to release ET toward the basolateral compartment, together with the capability of these peptides to influence events occurring in the interstitium, suggest that ET could also participate in interstitial inflammation. Data are now available that ET actually plays a role in the progression of chronic renal disease in different experimental models including renal mass reduction, lupus nephritis and streptozotocin-induced diabetes.