In chronic glomerulopathic disease, renal function correlates more with the degree oftubulointerstitial injury than that of the glomerular lesions. Proteinuria may be one of the pathologic links between these two intrarenal compartments. It is apparent that the proximal tubular epithelial cell (PTEC) assumes a proinflammatory and profibrotic role during proteinuria in which the PTEC expresses a variety of chemokines and injury signals that culminate in progressive interstitial inflammation and fibrosis. During diabetes, other substrates including advanced glycation end products (AGEs), AGE intermediates, and high glucose (HG) may provoke the PTEC even further. Glycated albumin, but not the equivalent dose of bovine serum albumin (BSA), stimulates tubular IL-8 and ICAM-1 expression via NF-κB-, MAPK- and STAT-1-dependent pathways. Human biopsies of diabetic nephropathy (DN) reveal colocalization of AGE and ICAM-1 in proximal tubules. The biologically active carbonyl intermediates methylglyoxal-BSA-AGE and AGE-BSA upregulate tubular expression of CTGF, TGF-β, and VEGF, whereas carboxymethyllysine-BSA stimulates tubular expression of IL-6, CCL-2, CTGF, TGF-β, and VEGF via RAGE activation and NF-κB signal transduction. Hyperglycemia (30 mM), but not the equivalent dose of mannitol, promotes proinflammatory (IL-6 and CCL-2), profibrotic (TGF-β) and angiogenic (VEGF) responses in tubular cells via MAPK and PKC signaling and induces epithelial mesenchymal transition, which is TGF-β1 mediated. It has recently been shown that toll-like receptor (TLR) is implicated in the diabetic kidney. In human DN biopsies and PTEC, TLR4is upregulated and plays a permissive role in HG-induced IL-6 and CCL-2 overexpression and monocyte transmigration. In streptozotocin-induced rat DN and PTEC, TLR2 appears to be upregulated. Other novel mediators that become activated in PTEC exposed to HG include macrophage inflammatory protein-3-α, Krüppel-like factor 6 and thioredoxin-interacting protein, which may be attenuated by peroxisome proliferator-activate dreceptor-γ activation. Collectively, these phenomena suggest that the renal tubules are heavily involved in the pathogenesis of DN. These pathophysiologic responses may be collectively described as diabetic tubulopathy.