FGF23: Possible kidney clearance role and time-course of the effects in phosphate homeostasis

Abstract

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates renal phosphate reabsorption by decreasing the expression of NaPi-IIa cotransporter in the brush border membrane (BBM) of renal proximal tubules, taking part in a hormonal axis which include vitamin D and parathyroid hormone (PTH) to maintain phosphate and calcium homeostasis. Several studies demonstrated a significant increase in plasma FGF23 levels in diseases which involve kidney failure or in renal nephrectomy, indicating a key role of the kidney in direct or indirect FGF23 clearance. Here we try to demonstrate: 1) if the kidney can directly clear FGF23 and 2) the time-course of the FGF23 effect in phosphate handling. For the first goal, we injected recombinant human FGF23 (rhFGF23) in normal rats and analyzed by immunofluorescence techniques whether we could detect it in kidney: no FGF23 was detected in renal cells, neither at 2 nor at 12 hours post administration probably at least in part of technical issues. For the second objective, blood, urine and kidneys were collected at several intervals after rhFGF23 administration. rhFGF23 showed a peak in plasma 2 h after injection, decreasing to less than a half after 6 h and to almost background levels after18 h. rhFGF23 was not detected in urine at any time point. After 6 h of FGF23 injection a decrease in NaPi-IIa (mRNA and protein) was observed in the kidney, in parallel with an enhanced urinary phosphate excretion. Although NaPi-IIa protein remained reduced 18 h post administration, its mRNA levels as well as urinary excretion of phosphate tended to return to their basal levels. No alterations in plasma phosphate levels were found in any of the groups. Furthermore, vitamin D receptor (VDR) protein expression was transiently decreased in the kidney, whereas no alterations in 24-hydroxylase (CYP24a1) were found. Measurements of FGF23 protein abundance in kidney were not valid, due to technical reasons. Thus, our findings are not conclusive regarding the possibility that FGF23 is filtered in the kidney and excreted in the urine. On the other hand, they indicate that the major action of FGF23 on phosphate excretion and NaPi-IIa expression takes place 6 h after injection, with urinary phosphate but not NaPi-IIa recovering to basal levels after 18 h.