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Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

¹ Department of Atherosclerosis and Diabetes, National Cardiovascular Center, Suita City, Osaka, Japan
² Department of Endocrinology and Metabolism, Kyoto University Graduate School of Medicine, Kyoto, Japan
³ National Cardiovascular Center Research Institute, Suita City, Osaka, Japan

Address correspondence and reprint requests to Shin-ichi Suga, MD, PhD, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita City, Osaka 565-8565, Japan. E-mail: s-suga{at}umin.ac.jp

Abbreviations: DG1, dystroglycan 1; GLEPP1, glomerular epithelial protein 1; HIF-1, hypoxia-inducible factor-1; VEGF, vascular endothelial growth factor

Glomerular injury plays a pivotal role in the development of diabetic nephropathy. To elucidate molecular mechanisms underlying diabetic glomerulopathy, we compared glomerular gene expression profiles of db/db mice with those of db/m control mice at a normoalbuminuric stage characterized by hyperglycemia and at an early stage of diabetic nephropathy with elevated albuminuria, using cDNA microarray. In db/db mice at the normoalbuminuric stage, hypoxia-inducible factor-1 (HIF-1), ephrin B2, glomerular epithelial protein 1, and Pod-1, which play key roles in glomerulogenesis, were already upregulated in parallel with an alteration of genes related to glucose metabolism, lipid metabolism, and oxidative stress. Podocyte structure-related genes, actinin 4 and dystroglycan 1 (DG1), were also significantly upregulated at an early stage. The alteration in the expression of these genes was confirmed by quantitative RT-PCR. Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria. In addition, HIF-1 protein expression was partially attenuated by pioglitazone. These results suggest that not only metabolic alteration and oxidative stress, but also the alteration of gene expression related to glomerulogenesis and podocyte structure, may be involved in the pathogenesis of early diabetic glomerulopathy in type 2 diabetes.

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