Terminal renal failure is the final common fate of chronic nephropathies regardless of the type of original insult. After removal of a critical number of nephrons, adaptive hemodynamic changes in the remaining nephrons ensure enough filtration power to the kidney but are ultimately detrimental. Such changes are largely mediated by the local formation of angiotensin II (AII) and prevented by the use of angiotensin-converting enzyme inhibitors, which also limit the forced opening of large unselective pores in the glomerular barrier, restoring size selectivity. Recent studies suggested that proteins filtered through the glomerular capillary, previously considered a marker of the severity of renal lesions, might have intrinsic toxicity on the proximal tubular cells and a contributory role in the progression of renal damage. Protein overload of proximal tubular cells induced the secretion of endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T expressed and secreted (RANTES) that was mainly directed toward the basolateral compartment of the cell. Evidence available in rat models of proteinuric renal disease shows that expression of genes encoding such vasoactive and proinflammatory molecules as ET-1, MCP-1, and RANTES was consistently upregulated, and synthesis of the corresponding peptides was enhanced in renal tissue. Additional mechanisms of proximal tubular cell activation leading to interstitial inflammation and matrix deposition are the filtration of protein-bound metals and hormones and deposition and activation of filtered complement. Limiting protein traffic and the biological effect of excessive tubular protein reabsorption by drugs interfering with AII synthesis or biological activity prevents renal disease progression.