Abstract: TH-PO681

Gene Expression Profiles of Glomeruli from BTBR ob/ob Mice Treated with Prolyl Hydroxylase Inhibitor Suggest Involvement of Extracellular Matrix Modulators in Pathogenesis of Diabetic Kidney Disease

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Sugahara, Mai, University of Tokyo, Tokyo, Japan
  • Tanaka, Tetsuhiro, University of Tokyo, Tokyo, Japan
  • Tanaka, Shinji, University of Tokyo, Tokyo, Japan
  • Fukui, Kenji, University of Tokyo, Tokyo, Japan
  • Shimizu, Akira, Nippion Medical School, Tokyo, Japan
  • Ishimoto, Yu, University of Tokyo, Tokyo, Japan
  • Inagi, Reiko, University of Tokyo, Tokyo, Japan
  • Nangaku, Masaomi, University of Tokyo, Tokyo, Japan
Background

We have previously shown that administration of prolyl hydroxylase (PHD) inhibitor, JTZ-951 (Japan Tobacco Inc.), improved glucose/lipid metabolism and decreased albuminuria in BTBR ob/ob mice (TH-PO450, ASN Kidney Week 2016). In order to elucidate the mechanism, we performed microarray gene expression analysis using isolated glomeruli.

Methods

Four-week-old male BTBR ob/ob mice were divided into the vehicle and JTZ-951 groups. JTZ-951 (0.005%; in feed) was administered from 4 weeks of age until euthanasia at 22 weeks. cDNA samples from isolated glomeruli were hybridized using Agilent SurePrint G3 Mouse GE Microarray 8x60K ver. 2.0.

Results

During the study period, mice in the JTZ-951 group tended to exhibit lower blood glucose levels (HbA1c: 8.9±0.3 vs 8.2±0.2%) and significantly lower total cholesterol levels (260±26 vs 164±19 mg/dL) with comparable food intake. JTZ-951 significantly decreased urinary albumin at 16 and 22 weeks (4.8±0.7 vs 1.9±0.4 and 5.9±1.3 vs 2.3±0.5 mg/mgCr, respectively) without affecting GFR. Podocyte and endothelial damages were markedly ameliorated in the JTZ-951 group. In gene expression analysis, 315 transcripts were upregulated and 150 were downregulated more than 3-fold in BTBR ob/ob mice compared to the wild type (WT). Among the 315 diabetes-upregulated genes, 102 revealed smaller increases in the JTZ-951 group (JTZ-951/WT<3). Similarly, the expression of 103 of the 150 diabetes-downregulated genes were restored in the JTZ-951 group (JTZ-951/WT>1/3). Pathway analysis of these 205 genes using Reactome database indicated that 5 out of the 25 top-ranked enriched pathways were related to extracellular matrix (ECM) organization and cell-matrix interactions; the corresponding entities included lysyl oxidase-like 2, thrombospondin 1, collagen type VIII alpha 1, bone morphogenetic protein 2, and CD44.

Conclusion

Long-term administration of JTZ-951 decreased albuminuria and ameliorated podocyte and endothelial damage, along with improvement in glucose/lipid metabolism. Microarray analysis revealed changes in the expression of genes associated with ECM, suggesting that ECM modulation within the glomerulus may play a role in the pathogenesis of diabetic kidney disease.

Funding

  • Commercial Support