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Abstract: SA-PO992

Inhibition of Hypoxia-Inducible Factor Hydroxylases in Proximal Tubules Alleviates CKD Progression After Ischemia-Reperfusion Injury

Session Information

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

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Sakashita, Midori, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Sugahara, Mai, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Tanaka, Tetsuhiro, Tohoku Daigaku, Sendai, Miyagi, Japan
  • Yanagita, Motoko, Kyoto Daigaku, Kyoto, Japan
  • Nangaku, Masaomi, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
Background

Hypoxia-inducible factor (HIF) is essential in many disease processes, including acute kidney injury (AKI) and the subsequent transition to chronic kidney disease (CKD). HIF-prolyl hydroxylase (HIF-PH) inhibitors stabilize HIF and promote erythropoietin (EPO) production; thereby currently utilized as a novel treatment for anemia in CKD patients. Systemic HIF activation alleviates acute ischemic kidney injury, but the role of HIF or HIF-PH inhibition in the proximal tubule during AKI-to-CKD transition remains unclear because of the difficulty in separating the possible beneficial effects of EPO on renal protection.
Since the proximal tubules are strongly damaged in AKI and the degree of injury, dedifferentiation, and regeneration play a major role in the pathogenesis of AKI to CKD, we aimed to determine the role of HIF and HIF-PH in the proximal tubules in the recovery period after AKI.

Methods

Ndrg1CreERT2/+: Phd1flox/flox/Phd2flox/flox/Phd3flox/flox mice were subjected to bilateral renal ischemia-reperfusion injury (IRI). Tamoxifen was administered for 5 consecutive days starting 2 days after IRI to induce proximal tubule-specific HIF-PH deletion. Four weeks after IRI, the kidney function and pathology were evaluated to assess the severity of CKD after AKI.

Results

The expression of proximal tubule-specific HIF-1α in the knockout mice was confirmed by highly sensitive immunohistochemistry. HIF-PH deletion after IRI resulted in lower creatinine levels, decreased albuminuria, and improved fibrosis on picro-Sirius red staining after 4 weeks compared to the control group. Plasma EPO and hematocrit levels were comparable between the knockout and control mice.

Conclusion

HIF-PH inhibition in the proximal tubules alleviated renal damage during the transition to CKD independent of EPO production.

Funding

  • Government Support – Non-U.S.