Kidney Week

Abstract: FR-OR70

Metabolomic Insights into Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors' Kidney Protection in Contrast-Induced Nephropathy

Session Information

• Innovative AKI Strategies and Drug Discoveries
  October 25, 2024 | Location: Room 7, Convention Center
  Abstract Time: 05:30 PM - 05:40 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Tani, Takashi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Takashi Tani, MD, PhD

• Tani, Hitomi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Hitomi Tani, MD, PhD

• Mii, Akiko, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Akiko Mii, MD, PhD

• Nakazato, Rei, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Rei Nakazato, MD

• Kamijo, Natsumi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Natsumi Kamijo, MD

• Shimizu, Akira, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Akira Shimizu, MD, PhD

• Sakai, Yukinao, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Yukinao Sakai, MD, PhD

Background

Contrast-induced nephropathy (CIN) is an acute kidney injury (AKI) associated with the use of contrast medium. We have recently reported that administration of HIF prolyl hydroxylase (HIF-PH) inhibitor, enarodustat play a protective role in rat model of CIN, suggested by improved renal dysfunction, 24-hour creatinine clearance levels and histopathological findings compared to a vehicle-treated group. HIF-PH inhibitors are thought to restore tissue homeostasis under anaerobic conditions by activating HIF1α, 2α, contributing to organ-protective effects. This study aimed to elucidate the mechanism through metabolomics analysis.

Methods

Sprague-Dawley rats were assigned to sham (Nx-S), vehicle-treated CIN (Nx-V), or drug-treated CIN (Nx-E) groups. At 15 weeks, Nx-V and Nx-E underwent right nephrectomy. Enarodustat or vehicle was given at 10 mg/kg for 3 days pre-CIN induction. At 17 weeks, CIN was induced, and rats were sacrificed 2 days later for kidney metabolomic analysis.

Results

CE-TOFMS and CE-QqQMS metabolomic analysis differentiated Nx-S from CIN groups (Nx-V and Nx-E). Nx-S maintained normal purine metabolism, implied by abundance of sedoheptulose 7-phosphate, hypoxanthine, and uric acid. In contrast, Nx-V and Nx-E showed elevated urea and amino acid metabolites, such as N-carbamoylaspartic acid, indicating nitrogen waste management due to kidney injury. Oxidative stress response was suggested by increased glutathione (GSH and GSSG) levels in CIN groups. PLS analysis revealed Nx-E had higher levels of metabolites involved in energy metabolism, purine metabolism, and cellular repair, like serine, aspartic acid, and hydroxyproline, suggesting enarodustat’s renoprotective effects. Additionally, reduced levels of creatinine and phosphocreatine in Nx-E implied decreased renal stress byproducts. Changes in citric acid cycle intermediates, such as citric acid and isocitric acid, in Nx-E suggested improved mitochondrial function and energy production.

Conclusion

This study has clarified the biochemical changes from contrast medium and enarodustat’s modulation. Enarodustat appeared to promote a metabolic shift aiding renal recovery post-CIN. Elevated metabolites related to energy and repair in Nx-E suggested enhanced AKI protection. Reduced stress-linked metabolites supported HIF-PH inhibitors’ therapeutic potential in CIN.

Funding

• Government Support – Non-U.S.