Background: Statins elicit antioxidant effects independently of their lipid-lowering properties. Heme oxygenase-1 (HO-1) induction may be a part of these pleiotropic effects, which are insufficiently described in the kidney. We hypothesize that simvastatin (SIM) transcriptionally activates HO-1 that protects renal proximal tubule cells from lipotoxic injury. Methods: Impact of SIM on 100 μmol/l oleic acid (OA)-mediated reactive oxygen species (ROS) production and consequent oxidative stress (4-hydroxynonenal (HNE) content) as well as cell injury/apoptosis (lactate dehydrogenase (LDH) release, caspase-3 activation) were determined in cultured renal proximal tubule (NRK52E) cells. Effect of SIM on the HO-1 promoter and its enhancer elements (antioxidant response element (ARE), CCAAT, AP1, and cAMP response element (CRE)) was also determined in reporter luciferase assays. Dominant-negative (dnMEK, M1CREB) and pharmacologic (H89) approaches were used to inhibit activation of extracellular signal regulated kinase (ERK), CREB, and protein kinase A (PKA), respectively. results: SIM dose-dependently activated the HO-1 promoter that was essential for protection against OA-dependent ROS production/oxidative stress and LDH release/caspase-3 activation. We found that the HO-1 promoter was induced through ERK and PKA-dependent activation of the CRE by SIM. conclusion: SIM may protect the kidney from adverse effects of circulating fatty acids by upregulating the antioxidant HO-1, aside from its well-described lipid-lowering effects.o besity is a growing problem among patients of all ages (1,2) that has a variety of effects on different organs including the kidney (3). Adverse effects of obesity are due to increased vascular reactivity, inflammation, and other factors called lipotoxicity (3). Obesity is associated with an elevation of circulating free fatty acids that are responsible for increased oxidative stress and subsequent lipotoxicity (3). Oleic acid (OA), a free fatty acid, is present in high concentration in the plasma of obese individuals (4). Previously, we showed that OA increases production of reactive oxygen species (ROS) that induces oxidative injury in renal proximal tubule cells (5).Statins-such as simvastatin (SIM)-are extensively used to lower dyslipidemia in children (6). Statins are not only lower lipids but also shown to exert "pleiotropic" effects that are not due to their lipid-lowering activity (7). For example, SIM transcriptionally activates the antioxidant HO-1 gene in the liver and NIH3T3 cells (8,9). It is plausible that such antioxidant properties can be used to diminish lipotoxic oxidative stress, caused by obesity. HO-1 induction-dependent renoprotective effects of SIM in a rat model of acute ischemia/reperfusion injury are noted (10) but the underlying mechanism and its potential role in obesity is unknown.Heme oxygenase-1 (HO-1) elicits adaptive responses against oxidative stress in the kidney (11). Oxidative stress transcriptionally induces the HO-1 promoter mostly via the antioxidant respon...