Authors
Lopez-Cayuqueo, K. I., Boivin, F. J., Cao, S., Leiz, J., Nassauer, L., Schambach, A., Hinze, C., Schmidt-Ott, K. M.
Abstract
Background: The renal medulla is characterized by a steep osmotic gradient that is essential for urinary concentration but may also influence cellular stress and injury responses. While vasopressin-dependent medullary hyperosmolarity is well established in water homeostasis, its role in shaping kidney injury and repair remains poorly understood. Methods: We pharmacologically reduced vasopressin signaling using the Avpr2 antagonist Tolvaptan and examined the consequences for renal medullary osmolality, tubular stress responses, inflammation, and fibrotic remodeling. Single-nucleus RNA sequencing, bulk transcriptomics, quantitative PCR, and histological analyses were performed in healthy kidneys and following unilateral ischemia-reperfusion injury (IRI) or cisplatin-induced nephropathy. Results: Tolvaptan treatment lowered renal medullary osmolality and suppressed osmotic stress-associated transcriptional programs in medullary collecting duct cells. Following IRI, Tolvaptan-treated mice exhibited attenuated expression of inflammatory and monocyte recruitment genes, reduced macrophage accumulation in the renal medulla, and diminished fibrotic remodeling at later stages. In cisplatin-induced nephropathy, Tolvaptan reduced tubular injury markers and inflammatory activation in the outer stripe of the outer medulla. Conclusions: These findings identify vasopressin-dependent renal medullary hyperosmolarity as a modulator of tubular stress, inflammation, and fibrotic remodeling after kidney injury. Modulation of the medullary osmotic environment influences early injury trajectories and downstream repair responses across distinct models of acute kidney injury.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 26 Oct 2026.
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