Altered gene expression related to glomerulogenesis and podocyte structure in early diabetic nephropathy of db/db mice and its restoration by pioglitazone.
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-1alpha (HIF-1alpha), 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 4alpha 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 4alpha, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria. In addition, HIF-1alpha 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.
Makino
Hisashi
H
Department of Atherosclerosis and Diabetes, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita City, Osaka 565-8565, Japan.
Miyamoto
Yoshihiro
Y
Sawai
Kazutomo
K
Mori
Kiyoshi
K
Mukoyama
Masashi
M
Nakao
Kazuwa
K
Yoshimasa
Yasunao
Y
Suga
Shin-ichi
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D036388:Ephrin-B2 / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007678:Kidney Glomerulus / Q000187:drug effects / Q000254:growth & development*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008820:Mice, Obese; D020411:Oligonucleotide Array Sequence Analysis; D000077205:Pioglitazone; D050199:Podocytes / Q000473:pathology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D045162:Thiazolidinediones / Q000494:pharmacology*
D051792:Basic Helix-Loop-Helix Proteins; D036388:Ephrin-B2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D000077205:Pioglitazone; D017027:Protein Tyrosine Phosphatases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D045162:Thiazolidinediones; C497443:Hif1a protein, mouse; C112923:Tcf21 protein, mouse; C516890:Ptpro protein, mouse