Low-molecular advanced glycation end-products (AGEs)-degradation products resulting from a proteolysis of tissue or circulating AGEs represent up to 80% of AGE plasma immunoreactivity. These AGE peptides contribute to the dramatic increase in AGE levels in end-stage renal disease even in the absence of diabetes. Because glomerular filtered AGE-degradation products may accumulate within intracellular compartments of proximal tubular epithelial cells, we investigated whether there is a pathway potentially mediating damaging effects of AGE-degradation products by perturbation of the function of the tubuloepithelium. Proximal tubular-derived rat kidney cells (IRPTC) were incubated with high-molecular AGEs highly modified by incubation of bovine serum albumin (BSA) with glucose for 50 days in vitro, and with low-molecular AGE-degradation products derived from proteolytic cleavage and isolated in the molecular range between 1 and 30 kDa. The proliferation of IRPTC (3H-thymidine incorporation) was reduced to 89+/-1% and 69+/-2% after 24 hr of incubation with BSA-AGE and BSA-AGE-degradation products, respectively. The cell viability of IRPTC was reduced significantly to 59+/-15% and 31+/-13% after 144 hr of incubation with BSA-AGE and BSA-AGE-degradation products, respectively. Conditioned media obtained from IRPTC incubated for 72 hr with BSA-AGE and its degradation products increased the proliferation rate of renal fibroblasts (RFb) to 222+/-24% and 449+/-40%, respectively. Incubation of IRPTC with BSA-AGE-degradation products increased the expression of endothelin-1 (ET-1) mRNA to 210% after 1 hr; the expression of platelet-derived growth factor-B (PDGF-B) mRNA reached 184% after 2 hr. Regarding the toxicity of AGEs to the kidney, low-molecular weight AGE-degradation products possibly form an individual fraction with a comparatively higher toxic potential.