Abstract: FR-PO640

Inhibition of Prolyl Hydroxylase Domain (PHD) Reduces Glomerular Macrophage Infiltration and Improves Albuminuria in Mice with a High Fat Diet

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Saito, Hisako, The University of Tokyo graduate School of Medicine, Tokyo, Japan
  • Tanaka, Tetsuhiro, The University of Tokyo graduate School of Medicine, Tokyo, Japan
  • Sugahara, Mai, The University of Tokyo graduate School of Medicine, Tokyo, Japan
  • Fukui, Kenji, The University of Tokyo graduate School of Medicine, Tokyo, Japan
  • Wakashima, Takeshi, The University of Tokyo graduate School of Medicine, Tokyo, Japan
  • Nangaku, Masaomi, the University of Tokyo School of Medicine, Tokyo, Japan
Background

The epidemic of obesity and its complications is rapidly growing all over the world. Chronic hypoxia in the tubulointerstitium is a major pathogenic factor mediating progression of CKD, and kidneys of metabolic disorders suffer from significant degrees of tubulointerstitial hypoxia. Recent drug discovery established utility of prolyl hydroxylase domain (PHD) inhibitors as stabilizers of hypoxia-inducible factors (HIFs) in vivo, which are currently in human clinical studies for the treatment of anemia in CKD. Notably some clinical studies suggest a role of PHD inhibitors in ameliorating obesity and hyperlipidemia. In this study, we hypothesized that HIF activation using a PHD inhibitor, JTZ-951, protects from obesity-related glomerulopathy (ORG) in mice fed with high fat diet (HFD).

Methods

Eight-week-old, C57BL/6J mice were fed with HFD for 12 or 20 weeks with or without JTZ-951 (0.005%; mixed in chow). Renal consequences of PHD inhibition was investigated at 20 or 28 weeks of age.

Results

JTZ-951 caused a transient rise in hematocrit levels (at 12 weeks of age). Successful activation of HIF in the kidney was confirmed by immunostaining for HIF-1α. Body weight was significantly lower in the JTZ-951 group as compared with the vehicle group. Plasma cholesterol levels were also significantly lower in the JTZ-951 group. PHD inhibition reduced albuminuria (120.8 vs 89.3 µg/mgCr, P<0.03). Histologically, glomerular tuft area, mesangial expansion and podocyte density were comparable between groups, but the number of F4/80- positive infiltrating macrophages was lower in the JTZ-951 group. Arginase 1 mRNA expression was higher in the JTZ-951 group, suggesting a possible role of PHD inhibition in altering macrophage polarity, which may have contributed to reducing albuminuria.

Conclusion

Activation HIF by PHD inhibitors mediated multiple renal and non-renal consequences in mice with HFD. JTZ-951 significantly improved obesity and lowered total cholesterol levels. In the kidney, a decrease in albuminuria was associated with decreases in infiltrating macrophages and their possible skewing toward the M2 phenotype. Results of the present study offer a promising view that pharmacological PHD inhibition may be beneficial for the treatment of CKD associated with obesity.