Intestinal paracellular phosphate absorption resists dietary adaptation but is upregulated in CKD
Zsuzsa Radványi, Laurine Lang, Nati Hernando, Carsten A WagnerAbstract
Background and hypothesis
The paracellular absorption of phosphate (Pi) contributes the bulk of intestinal absorption under conditions of high dietary Pi availability. Here, we hypothesized that dietary Pi content and reduced renal function affect intestinal paracellular Pi transport.
Methods
Wildtype male mice received low (<0.1%, LP) or high (1.2%, HP) diet for 7 days. Urine, blood, intestinal segments and kidneys were collected and analyzed for urinary and plasma concentrations of Pi and Ca2+, plasma levels of Pi-regulating hormones, evaluation of trans- and paracellular Pi transport across jejunum and ileum and intestinal claudin expression. Additionally, wildtype male mice underwent sham operation or 5/6 nephrectomy followed by 14 days of HP diet to mimic the pathophysiological features of CKD and intestinal Pi transport was assessed.
Results
Mice displayed the expected systemic adaptation to LP/HP diets but showed no differences in ileal paracellular Pi transport upon different dietary Pi. The protein expression of several barrier-associated claudins (claudin-3, -4 and -7) was upregulated upon HP diet, specifically in the ileum. 5/6 nephrectomized mice showed the expected disturbed mineral metabolism, lacked downregulation of active intestinal Pi transport, and showed higher ileal paracellular Pi transport. Claudin-3 and claudin-7 were mislocalized in the ileum. In human intestinal cells, the uremic toxin p-cresol enhanced Pi permeability.
Conclusion
Changes in dietary Pi intake do not alter paracellular Pi fluxes. In a mouse model of CKD, active intestinal Pi transport is not downregulated despite hyperphosphatemia and paracellular Pi fluxes elevated. The loss of junctional barrier integrity might be driven driven by uremic toxins such as p-cresol and could contribute to systemic phosphate imbalance in CKD. Our findings highlight the intestinal epithelial tight junction (TJ) and uremic toxins as potential therapeutic targets to prevent disturbed phosphate homeostasis in CKD.