Altered gene expression related to glomerulogenesis and podocyte structure in early diabetic nephropathy of db/db mice and its restoration by pioglitazone.

Abstract

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.

• Authors: Hisashi Makino, Yoshihiro Miyamoto, Kazutomo Sawai, Kiyoshi Mori, Masashi Mukoyama, Kazuwa Nakao, Yasunao Yoshimasa, Shin-ichi Suga
• Journal: Diabetes (Diabetes) Vol. 55 Issue 10 Pg. 2747-56 (Oct 2006) ISSN: 0012-1797 [Print] United States
• PMID: 17003339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Ephrin-B2
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Membrane Proteins
• Tcf21 protein, mouse
• Thiazolidinediones
• Protein Tyrosine Phosphatases
• Ptpro protein, mouse
• Receptor-Like Protein Tyrosine Phosphatases, Class 3
• Pioglitazone

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Diabetes Mellitus, Type 2 (physiopathology)
• Diabetic Nephropathies (physiopathology)
• Disease Models, Animal
• Ephrin-B2 (genetics)
• Gene Expression (drug effects)
• Gene Expression Profiling
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics)
• Kidney Glomerulus (drug effects, growth & development)
• Membrane Proteins (genetics)
• Mice
• Mice, Obese
• Oligonucleotide Array Sequence Analysis
• Pioglitazone
• Podocytes (pathology)
• Protein Tyrosine Phosphatases (genetics)
• Receptor-Like Protein Tyrosine Phosphatases, Class 3
• Thiazolidinediones (pharmacology)