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Kidney Week

Abstract: FR-PO125

Multiple, Systemic Effects of PHD Inhibitors Signify an Anti-Fibrotic and Anti-Inflammatory Impact on Cardiovascular Complications in the Remnant Kidney

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Uchida, Lisa, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Tanaka, Tetsuhiro, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Saito, Hisako, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Sugahara, Mai, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Fukui, Kenji, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Wakashima, Takeshi, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Nangaku, Masaomi, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
Background

Hypoxia plays a crucial role in the progression of chronic kidney disease(CKD) which is associated with fibrosis, inflammation and oxidative injury. Previous studies suggest that prolyl hydroxylase inhibitors(PHD inhibitors), stabilizers of hypoxia-inducible factors (HIFs), could be applied in acute organ injuries like renal ischemia-reperfusion and myocardial infarction. However, the effect of PHD inhibitor on CKD and its cardiovascular consequences remains unknown.

Methods

Male Sprague-Dawley rats underwent 5/6 nephrectomy (remnant kidney: RK). Rats were divided into three groups: (1)sham operation rats (2)RK rats with normal diet (3) RK rats with 0.005% enarodustat(PHD inhibitor) diet since 1 week before 5/6 nephrectomy. L-NNA(20 mg/L), NO synthase inhibitor, was supplemented in drinking water to accelerate the CKD model. At 6 weeks after 5/6 nephrectomy, kidney and heart were harvested after the echocardiography.

Results

Systolic blood pressure was lower in RK-Enarodustat group than in the RK group, but the difference did not reach statistical significance. Blood urea nitrogen and serum creatine levels at 2, 4, 6 weeks were reduced in the RK-Enarodustat group, whereas there was no difference in urinary protein excretion between the two groups. The number of ED-1-positive cells was significantly less in the RK-Enarodustat group (43.7±7.7 per ×200 field) than in the RK group (100.8±14.2, P<0.01). And, the number of infiltrated CD206 macrophages, the M2 macrophages, was also less in the RK-Enarodustat group. Immunohistochemical analysis revealed a significant decrease in nitrotyrosine accumulation in tubules in the RK-Enarodustat group(7.6±1.3 vs 11.5±0.9, p=0.036). In heart, the number of ED-1, CD206-positive infiltrating macrophages and picrosirius red staining showed significant reductions in the RK-Enarodustat group. Anterior and posterior wall thicknesses, markers for cardiac hypertrophy, were markedly less in the RK-Enarodustat group than in the RK group, whereas there was no difference in fractional shortening, ejection fraction and E/A.

Conclusion

These data show that PHD inhibitors significantly improve inflammation, oxidative stress and fibrosis in remnant kidney and may also mediate beneficial effects in cardiovascular complications.