Towards Identification of Tight Junction Components Involved in the Intestinal Paracellular Absorption of Phosphate

Inorganic phosphate (Pi) is essential for numerous physiological processes, yet both its deficiency and excess are associated with severe skeletal and cardiovascular complications. While renal Pi handling is well-characterized, considerably less is known about the regulation and molecular identity of the intestinal paracellular Pi absorption, despite this pathway reportedly mediating the majority of Pi transport in those consuming a Western diet. Here, we investigated the individual contribution of tight junction (TJ) proteins claudin-3 and claudin-4, as well as the potential regulation of dietary Pi intake and chronic kidney disease (CKD) on intestinal paracellular Pi absorption. We demonstrate that passive Pi absorption does not functionally adapt to dietary Pi content in the gut. In contrast, CKD induces enhanced ileal paracellular Pi permeability, potentially due to TJ remodeling triggered by uremic toxins. While the global deletion of claudin-3 did not affect intestinal Pi absorption or systemic Pi handling, it resulted in elevated plasma calcitriol levels but reduced calcitriol responsiveness. Claudin-4 seems to exert cell type-specific effects when depleted or overexpressed in vitro. Conversely, intestine-specific Cldn4 KO mice displayed increased paracellular permeability specifically for Pi, as well as elevated plasma Pi, endocrine dysregulation and impaired bone mineralization. These findings identify claudin-4 as a physiologically relevant TJ component restricting intestinal Pi permeability under normal dietary conditions. Collectively, our work establishes intestinal TJ composition as a functional determinant of paracellular Pi permeability and systemic Pi homeostasis. Selective modulation of TJ proteins might offer novel therapeutic approaches to reversing or preventing hyperphosphatemia and its deleterious consequences.

Author dc:creator

• Radvanyi, Zsuzsa

• 610 Medicine & health
• 570 Life sciences; biology

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng