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

Abstract

Introduction: Arginine vasopressin receptor 2 (AVPR2) signaling regulates kidney collecting duct signaling and urinary concentration, but the kidneys 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.