Work

AVPR2 antagonism with tolvaptan alters medullary cell responses and attenuates kidney injury

Year: 2026

Type: preprint

Abstract: ABSTRACT Introduction Arginine vasopressin receptor 2 (AVPR2) signaling regulates kidney collecting duct signaling and urinary concentration, but the kidney’s cell-type-specific responses to its pharmacological inhibition and their relevance to non-cystic kidney injury remain incompletely characterized. Methods We examined physiological and transcriptional responses to the AVPR2 antagonist Tolvaptan in uninjured male mice and assessed tissue outcomes after unilateral ischemia-reperfusion injury (IRI) and repeated cisplatin administration. Analyses included renal tissue osmolality measurements, single nucleus and bulk RNA sequencing of kidney tissues, quantitative PCR, in situ hybridization, and histology. Results In uninjured kidneys, Tolvaptan reduced urine and medullary tissue osmolality and altered transcription predominantly in medullary collecting-duct populations, including lower expression of selected stress-associated and proinflammatory genes. 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. In cisplatin-induced kidney injury Tolvaptan reduced tubular injury markers and inflammatory activation in the outer medulla. Conclusions Tolvaptan attenuates medullary tubular stress responses and post-injury inflammation and fibrosis. These findings extend the effects of pharmacological AVPR2 antagonism beyond water homeostasis to tissue-level responses in non-cystic kidney injury. TRANSLATIONAL STATEMENT Acute kidney injury can lead to persistent inflammation and fibrotic remodeling, yet the contribution of medullary Avpr2 signaling to these processes remains poorly understood. In mice, treatment with the clinically used Avpr2 antagonist Tolvaptan reduced medullary osmolality and modulated stress-associated tubular transcriptomes. Tolvaptan treatment initiated before injury reduced selected inflammatory and tissue remodeling endpoints in experimental kidney injury. These findings support further investigation of pharmacological AVPR2 antagonism in non-cystic kidney disease.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.21.760644