Abstract: FR-PO835
Hypoxia-Inducible Factor (HIF) Activation in Podocytes Exacerbates Crescentic Glomerulonephritis
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Kurata, Yu, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo-ku, Tokyo, Japan
- Tanaka, Tetsuhiro, Tohoku Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Sendai, Miyagi, Japan
- Sugahara, Mai, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo-ku, Tokyo, Japan
- Mimura, Imari, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo-ku, Tokyo, Japan
- Nangaku, Masaomi, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Naikagaku Senko Jinzo Naibunpi Naika, Bunkyo-ku, Tokyo, Japan
Background
Hypoxia-inducible factor (HIF) is a transcription factor that mediates cellular responses to hypoxia. Although various studies have explored the effects of HIF activation in renal diseases, the role of HIF in podocytes remains unclear. We established podocyte-specific HIF-prolyl hydroxylase (PH) 1/2/3 conditional knockout mice, in which HIF was specifically activated in podocytes. To examine the role of HIF activation in podocytes during glomerular injury, we subjected these mice to crescentic glomerulonephritis induced by nephrotoxic serum (NTS).
Methods
We crossed Podocin-Cre mice with HIF-PH1/2/3 triple-floxed mice to generate podocyte-specific HIF-PH1/2/3 conditional knockout (KO) mice. Cre-negative littermates were used as controls (WT mice). Crescentic glomerulonephritis was induced by the intravenous administration of NTS (1.2 μL/g). NTS was produced by immunizing sheep with isolated rat glomeruli.
Results
First, we confirmed podocyte-specific HIF-1 activation in KO mice by immunohistochemical staining. There were no significant differences in the histological findings of the kidney, kidney function, and urinary albumin levels between WT and KO mice. Next, we induced nephrotoxic serum nephritis (NTN). On day 7, KO mice exhibited significantly higher urinary albumin levels th WT mice. Histological analysis revealed exacerbated glomerular crescent formation and tuft necrosis in KO mice. The number of Ki-67-positive parietal epithelial cells (PECs) and CD44-positive glomeruli significantly increased in KO mice. Glomerular deposition of sheep IgG and mouse IgG was similar in WT and KO mice. To further investigate the underlying mechanism, we conducted bulk RNA-seq of the isolated glomeruli. Comparison of WT and KO mice subjected to NTN identified a total of 167 differentially expressed genes (DEGs). Enrichment analysis revealed that the DEGs were significantly enriched in leukocyte chemotaxis, DNA-templated DNA replication, positive regulation of cell death, regulation of leukocyte activation, and positive regulation of cell migration.
Conclusion
HIF activation in podocytes worsened glomerular injury in a crescentic glomerulonephritis model. Aggravated inflammatory responses and excessive PEC activation may exacerbate glomerular injury.
Funding
- Government Support – Non-U.S.