The early stages of nephropathy in obese, diabetic, dyslipidemic (ZS) rats are characterized by tubular lipid accumulation and pervasive inflammation. Our prior work has shown that these events are interrelated. We now tested the hypothesis that proximal tubules from ZS obese diabetic rats in vivo, and cultured proximal tubule cells (NRK52E) exposed to oxidized LDL (oxLDL), changed their normally quiescent epithelial phenotype into a proinflammatory phenotype. Urine of obese diabetic rats contained more lipid peroxides, and LOX-1, a membrane receptor that internalizes oxidized lipids, was mobilized to luminal sites. Levels of the intercellular adhesion molecule-1 (ICAM-1) and focal adhesion kinase (FAK), which participate in leukocyte migration and epithelial dedifferentiation, respectively, were also upregulated in their tubules. NRK52E cells exposed to oxLDL showed similar modifications, plus suppression of anti-inflammatory transcription factor PPAR delta. In addition, oxLDL impaired epithelial barrier function. These alterations were prevented by an anti-LOX-1 antibody. The data support the concept that tubular LOX-1 activation driven by lipid oxidants in the pre-urine fluid is critical in the inflammatory changes. We suggest that luminal lipid oxidants leaked from damaged glomeruli may be partly responsible for the renal tubulo-interstitial injury of obesity, diabetes and dyslipidemia.