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Kidney Week

Abstract: SA-PO068

The Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Enarodustat Protects the Kidney From Contrast-Induced Nephropathy

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tani, Takashi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Tani, Hitomi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Mii, Akiko, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan
Background

Contrast-induced nephropathy (CIN) is an acute kidney injury (AKI) associated with the use of contrast medium. Vasoconstriction, oxidative stress, and hypoxic environment are considered the main causes of CIN. At under anaerobic conditions, hypoxia-inducible factors (HIFs) serve to restore tissue homeostasis by stimulating erythropoiesis, angiogenesis, and anaerobic glycolysis. HIF prolyl hydroxylase (HIF-PH) inhibitors stabilize HIFs, and then recent studies demonstrate that these drugs show protective effects on kidneys from renal ischemia/reperfusion injury, cisplatin-induced AKI, and diabetic kidney disease. In this study, we sought to show that the use of HIF-PH inhibitors plays a protective role in an animal model of CIN.

Methods

Sprague-Dawley rats were randomly allocated into sham-operated group (n=5), vehicle-treated CIN group (vehicle group; n=7), and drug-treated CIN group (enarodustat group; n=6). At 15-week-old, the right nephrectomy was performed. Enarodustat or vehicle was administered daily by oral gavage at a dose of 10 mg/kg from 3 days before the operation day to the induction of CIN. At 17-week-old, the rats were anesthetized and indomethacin (10 mg/kg) and L-NAME (10 mg/kg) were injected. After 30 min, rats were then injected intravenously with iopamidol (OYPALOMIN, 3.7 g iodine/kg). Rats were sacrificed 2 days after surgery.

Results

Hemoglobin and hematocrit levels were comparable in all groups. Significant elevation of blood urea nitrogen, serum creatinine, and decreases in 24hr creatinine clearance levels were observed in vehicle group, whereas those parameters were comparable in enarodustat group to sham-operated group. Kidney tissue mRNA expression of Ngal, Kim-1, and TNF-α were all markedly elevated in vehicle group, which were ameliorated by administration of enarodustat. Histopathological examination disclosed severe findings in the kidney of CIN rats, characterized by proteinaceous casts in tubuli, medullary congestion, and hemorrhage in the outer zone inner stripe of medulla, and tubular necrosis in the outer zone outer stripe of medulla. Administration of enarodustat attenuated these histopathological findings.

Conclusion

These results showed that HIF-PH inhibitor enarodustat protects the kidney from CIN in a rat model. HIF-PH inhibitors may be potential therapeutic agents for clinical CIN.

Funding

  • Government Support – Non-U.S.