Renal tubular epithelial cells mimic endothelial cells upon exposure to oxidized LDL

In protein-uric states, renal tubular epithelial cells are exposed to diverse macromolecules, including low-density lipoproteins (LDL), normally excluded from the urinary space. Oxidized LDL (LDL_OX) is incriminated in atherogenesis and glomerulosclerosis. Since urine is prooxidant, we considered whether LDL_OX injures renal tubular epithelial cells (LLC-PK₁). We demonstrate that the cytotoxicity of LDL_OX on LLC-PK₁ cells resembles its toxicity to human umbilical vein endothelial cells (HUVEC) in that oxidized but not native LDL is injurious. Pretreatment of LLC-PK₁ cells and HUVEC with antioxidants markedly reduced the cytotoxicity of LDL_OX. Pretreatment of LDL with antioxidants, prior to oxidation of LDL, vitiated its cytotoxicity. That LDL_OX is prooxidant was supported by expression of heme oxygenase, a redox-sensitive enzyme. LDL_OX induced heme oxygenase mRNA and enzyme activity. Pretreatment of LDL with antioxidants prior to oxidation attenuated heme oxygenase mRNA induction in LLC-PK₁ and HUVEC. An iron chelator prevented cytotoxicity and heme oxygenase expression induced by LDL_OX. Based on these effects of LDL_OX, we draw an analogy between tubulointerstitial disease and atherogenesis and speculate that LDL_OX contributes to tubulointerstitial disease in proteinuric states.