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

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.

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.

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.

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.