Abstract: FR-PO144
Investigating Vasopressin-Dependent Renal Medullary Osmolarity as a New Target for Renoprotection
Session Information
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- López-Cayuqueo, Karen I., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
- Boivin, Felix, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
- Leiz, Janna, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
- Cao, Shuang, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
- Hinze, Christian, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
- Schmidt-Ott, Kai M., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
Group or Team Name
- Molecular Mechanisms of Kidney and Kidney Transplant Diseases.
Background
The renal medulla is characterized by a hyperosmolarity that depends on Avpr2 signaling. High osmolarity in the kidney medulla is required for urine concentration mechanisms. However, the role of the hyperosmolar medulla beyond electrolyte-free water reabsorption is not well understood. Here, we investigate the role of high osmolality in regulating kidney injury responses at molecular and cellular levels.
Methods
We analyzed kidneys from C57Bl/6N mice treated with tolvaptan (Avpr2 antagonist) and compared them to kidneys from control mice. Our analysis included single-nuclei and bulk RNA sequencing, in situ hybridization, and renal ischemia-reperfusion injury.
Results
Tolvaptan treatment reduced renal medullary osmolality and caused significant changes in the gene expression of tubular cells in the renal medulla. These changes included decreased expression of stress response and immune activation-related genes (such as Atf4, Ddit3, Hmgb1) and genes influenced by high tissue osmolality (such as Cryab, and Nupr1). The results were confirmed through bulk RNA sequencing and in situ hybridizations. Avpr2 antagonist treatment protected the renal medulla from fibrosis following unilateral renal ischemia-reperfusion injury.
Conclusion
Applying unbiased single-cell transcriptomics and orthogonal validation, we discovered that inhibiting Avpr2 in mice reduced the expression of osmolarity-regulated genes in tubular cells of the renal medulla, including those associated with stress and immune responses. Avpr2 inhibition protected the renal medulla from fibrosis development following ischemia-reperfusion injury. These findings suggest that targeting Avpr2-dependent medullary osmolality could be a potential strategy for renoprotection.
Funding
- Government Support – Non-U.S.