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Am J Physiol Renal Physiol 286: F913-F921, 2004. First published January 13, 2004; doi:10.1152/ajprenal.00323.2003
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Adipose differentiation-related protein and regulators of lipid homeostasis identified by gene expression profiling in the murine db/db diabetic kidney

Rangnath Mishra,1 Steven N. Emancipator,2 Casey Miller,3 Timothy Kern,3 and Michael S. Simonson1

Divisions of 1Nephrology and 3Endocrinology, Department of Medicine, and 2Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106

Submitted 5 September 2003 ; accepted in final form 7 January 2004

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.

transcriptome; diabetes; microarray; peroxisome proliferator-activated receptor-{alpha}


Address for reprint requests and other correspondence: M. S. Simonson, Dept. of Medicine, Div. of Nephrology, Biomedical Research Bldg., Rm. 427, Case Western Reserve Univ., 2065 Adelbert Rd., Cleveland, OH 44106 (E-mail: mss5{at}po.cwru.edu).




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