Abstract: SA-PO491
Prolyl Hydroxylase Domain Inhibitor Protects Against Metabolic Disorder-Related Kidney Disease by Suppressing Monocyte Chemoattractant Protein 1 Expression in Mesangial Cells
Session Information
- Diabetic Kidney Disease: Basic - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Sugahara, Mai, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Tanaka, Shinji, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Ishimoto, Yu, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Fukui, Kenji, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Shimizu, Akira, Nippion Medical School, Tokyo, Japan
- Inagi, Reiko, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Yamauchi, Toshimasa, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Kadowaki, Takashi, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Nangaku, Masaomi, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Tanaka, Tetsuhiro, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
Background
We previously showed that administration of a prolyl hydroxylase domain (PHD) inhibitor, enarodustat, improved glucose/lipid metabolism and restored adiponectin levels in BTBR ob/ob mice. It also reduced albuminuria and ameliorated glomerular epithelial and endothelial damage (TH-PO450, ASN Kidney Week 2016). To elucidate the mechanism of renoprotection, we performed transcriptome analysis of isolated glomeruli and in vitro experiments using murine mesangial cells.
Methods
Four-week-old male BTBR ob/ob mice were divided into vehicle and enarodustat groups. Enarodustat (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. SV40 MES 13 cells were stimulated by palmitate with either enarodustat or AdipoRon (adiponectin receptor agonist).
Results
Enarodustat-treated mice tended to exhibit lower blood glucose (HbA1c: 8.9±0.3 vs 8.2±0.2%, p = 0.060) and significantly lower total cholesterol levels (260±26 vs 164±19 mg/dl, p = 0.019) with comparable intake. Plasma adiponectin was increased in enarodustat-treated mice (6.7±0.6 vs 9.8±0.8 ng/ml, p = 0.014). Enarodustat significantly decreased albuminuria (5.9±1.3 vs 2.3±0.5 mg/mgCr, p = 0.017) without affecting GFR. Electron microscopic examination revealed amelioration of glomerular epithelial and endothelial damage in enarodustat-treated mice. Transcriptome analysis of isolated glomeruli revealed reduced expression of monocyte chemoattractant protein-1 (MCP-1) in enarodustat-treated mice. Urinary MCP-1 was decreased in enarodustat-treated mice (317±62 vs 173±25 pg/mgCr, p = 0.064), accompanied by reduced glomerular macrophage infiltration (2.7±0.5 vs 1.1±0.2/glomerulus, p = 0.006). In vitro experiments demonstrated that both enarodustat and AdipoRon suppressed palmitate-induced MCP-1 production in mesangial cells. Enarodustat’s suppressive effect was abolished when HIF-1α was knocked down by siRNA.
Conclusion
Enarodustat conferred renoprotection through both indirect and direct pathways: improvement in glucose/lipid metabolism and suppression of MCP-1 production in mesangial cells via HIF-1 activation.
Funding
- Commercial Support –