Renal Phosphate Reabsorption in Humans Depends on at Least Three Distinct Transporters Unlike in Mice

AIM: Kidney excretion of phosphate is the gatekeeper of systemic phosphate homeostasis as evident from inborn and acquired diseases. Renal phosphate transporters are a promising target for phosphate-lowering drugs, but molecular details of human kidney phosphate handling are largely unknown. Here, we aim to understand the dependency of renal phosphate transport on species, age, and sex. METHODS: We used a combination of transporter-specific inhibitors and radioactive flux measurements in isolated BBM vesicles prepared from human and murine kidneys. We included human female and male neonates (0-11 months) and adults (51-63 years) and age-matched mouse kidneys. Immunoblotting and immunofluorescence detected transport protein expression, and transcript expression was analyzed in publicly available data. FINDINGS: The flux experiments revealed that in human kidneys SLC34A1, SLC34A2/3 and other non-SLC34 transporter are active and expressed with age- and sex-dependent differences. In mice about 80% of renal phosphate handling depends on Slc34a1, but in humans SLC34A1 contribution is 60% in neonates and only 40% in adults. SLC34A3 contribution accounts for 20% in human neonates and 40% in human adults but is almost negligible in mice. Non SLC34 sodium-dependent phosphate transport was around 20% in all groups. SCRNA-seq data and immunoblotting analysis revealed differences in sodium cotransporters between species that supported the activity measurements. CONCLUSION: Our data provide the first direct measurement of sodium-phosphate cotransporter activities in human kidney and show profound differences between species. These results are critical when developing novel drugs to modulate renal phosphate reabsorption.