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1 Department of Medicine, Division of Nephrology, Case Western Reserve University, Cleveland, OH, USA
2 Department of Pathology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA
3 Department of Endocrinology, Case Western Reserve University, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: mss5{at}po.cwru.edu.
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 versus non-diabetic db/m kidneys, a time characterized by hyperglycemia but by little renal histopathology. By 16 weeks significant mesangial expansion and tubulointerstitial injury 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 up-regulated 5.4-fold in 16 week 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 the peroxisome proliferatoractivated
receptor
(PPAR) has been shown to regulate their expression in adipocytes. In our
experiments, PPAR mRNA was elevated in db/db diabetic kidneys, and PPAR protein was
up-regulated 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.
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