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

In proteinuric 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 anti-oxidants, 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.