EVIDENCE SUGGESTING THAT NITRIC-OXIDE MEDIATES IRON-INDUCED TOXICITY IN CULTURED PROXIMAL TUBULE CELLS

The potential role of nitric oxide (NO) in iron-induced toxicity was s tudied in proximal tubule cells in primary culture. NO production (NO2 -/NO3-) was significantly increased in iron-treated compared with cont rol cells (3.43 +/- 0.08 vs. 1.56 +/- 0.08 nmol/dish, P < 0.01). NO sy nthase (NOS) activity was also induced by iron treatment; (16.2 +/- 2. 0 vs. 0.4 +/- 0.2 nmol of [H-3]citrulline/mg protein, P < 0.01). L-Arg inine, a substrate for NOS, augmented iron-induced PTO production and cell damage [lactate dehydrogenase (LDH) leakage], whereas aminoguanid ine, an inhibitor of NOS, reduced iron-induced NO production and LDH l eakage. Sodium nitroprusside, an exogenous NO donor, induced LDH leaka ge in a dose-dependent manner, but no effect on lipid peroxidation [ma londialdehyde bis[dimethyl acetal] (MDA) production] was observed. Sup eroxide dismutase and catalase decreased iron-induced MBA production h ut did not affect LDH leakage or NO production. Dimethylpyrroline N-ox ide and desferal prevented MDA production, LDH leakage, and NO product ion. We concluded that NO is one of the mediators of iron-induced toxi city in proximal tubule cells. NO-induced toxicity is not dependent on lipid peroxidation. This may explain the variable effect of different antioxidants on eel damage and lipid peroxidation in iron-induced cyt otoxicity.