We investigated the molecular basis of progressive diabetic renal injury in db/db mice by profiling kidney gene expression. Using high-density microarrays, we identified 482 RNA transcripts differentially expressed in 8-wk db/db vs. nondiabetic db/m kidneys, a time characterized by hyperglycemia but by little renal histopathology. By 16 wk significant mesangial expansion had developed. Sixteen-week db/db kidneys differentially expressed 639 RNA transcripts. Diabetic kidneys specifically expressed several genes normally found in adipocytes, including adipocyte differentiation-regulated protein (ADRP; or adipophilin in humans). ADRP mRNA was specifically upregulated 5.4-fold in 16-wk db/db kidneys. This finding was confirmed at the protein level by Western blotting, and immunohistochemistry localized ADRP diffusely to tubular epithelium throughout the cortex. ADRP is a perilipin family protein that forms lipid storage vesicles and controls triglyceride utilization; we showed that accumulation of lipid storage droplets correlated with the magnitude and localization of ADRP in db/db kidneys. Other genes involved in lipid transport, oxidation, and storage were differentially regulated in db/db kidneys, and peroxisome proliferator-activated receptor-alpha (PPAR alpha) has been shown to regulate their expression in adipocytes. In our experiments, PPAR alpha mRNA was elevated in db/db diabetic kidneys, and PPAR alpha protein was upregulated in glomeruli, cortical tubules, and renal arterial vessels of db/db mice. In conclusion, these studies furnish new RNA-based data for mechanistic investigation into renal injury in the diabetic kidney and identify a switch of kidney phenotype in favor of lipid accumulation in diabetic kidney.