Kidney Week

Abstract: TH-PO0263

Inhibition of Hypoxia-Inducible Factor-Prolyl Hydroxylase in Proximal Tubules Lowers Systemic Blood Pressure by Upregulating the Renal Expression of Adrenomedullin

Session Information

• Hypertension and CVD: Mechanisms
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Maruno, Sayako, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo, Tokyo, Japan

Sayako Maruno, MD, PhD

• Sugahara, Mai, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo, Tokyo, Japan

Mai Sugahara, MD, PhD

• Sakashita, Midori, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo, Tokyo, Japan

Midori Sakashita, MD, PhD

• Numata, Genri, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Junkanki Naika, Bunkyo, Tokyo, Japan

Genri Numata, MD, PhD

• Takimoto, Eiki, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Junkanki Naika, Bunkyo, Tokyo, Japan

Eiki Takimoto, MD, PhD

• Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto Prefecture, Japan

Motoko Yanagita, MD, PhD

• Tanaka, Tetsuhiro, Tohoku Daigaku Daigakuin Igakukei Kenkyuka Igakubu Jin Koketsuatsu Naibunpigaku, Sendai, Miyagi Prefecture, Japan

Tetsuhiro Tanaka, MD, PhD, FASN

• Nangaku, Masaomi, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo, Tokyo, Japan

Masaomi Nangaku, MD, PhD

Background

Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular responses to hypoxia. The role of HIF in kidney diseases, especially in the chronic phase, remains largely elusive, partly because HIF has cell type-specific functions. This underscores the need for elucidating the distinct role of HIF in each cell population within the kidney. In this study, we explored the role of HIF in proximal tubular cells by using proximal tubule-specific HIF-prolyl hydroxylase (HIF-PH, also known as PHD) knockout mice.

Methods

Proximal tubule-specific Phd1-2-3 conditional knockout mice (Ndrg1^CreERT2/+: Phd1-2-3^flox/flox mice (Phd cKO)) were generated by crossbreeding N-myc downstream regulated gene-1 (Ndrg1) ^CreERT2/+ mice and Phd1-2-3^flox/flox mice. Cre-negative mice were used as controls.

Results

Tamoxifen treatment induced HIF-1α accumulation in proximal tubules in Phd cKO mice. Body weight, hematocrit, and serum creatinine were comparable between Phd cKO and control mice. No morphological changes were observed in the kidney. Surprisingly, Phd cKO mice had lower blood pressure compared to the control mice (mean blood pressure: 59.89±2.01(Phd cKO) vs. 77.96±2.47 mmHg (control), p<0.001). Urinary albumin was decreased in Phd cKO mice. In the kidney of Phd cKO mice, there was an increase in the expression of adrenomedullin, a peptide known for its vasodilative and natriuretic effects. The administration of an adrenomedullin antagonist normalized the blood pressure of Phd cKO mice. There was no difference in plasma adrenomedullin concentrations between Phd cKO and control mice, suggesting that adrenomedullin worked in an autocrine or paracrine manner within the kidney, not as a circulating hormone, to induce the change in systemic blood pressure. Since no apparent change was observed in urinary sodium excretion, further investigation is needed to clarify the precise mechanism.

Conclusion

HIF-PH inhibition in proximal tubules lowers systemic blood pressure by upregulating the renal expression of adrenomedullin.

Funding

• Government Support – Non-U.S.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025n6yq45th