Endocrine regulation of MFS2 by branchless controls phosphate excretion and stone formation in Drosophila renal tubules

Abstract

How inorganic phosphate (Pi) homeostasis is regulated in Drosophila is currently unknown. We here identify MFS 2 as a key Pi transporter in fly renal (Malpighian) tubules. Consistent with its role in Pi excretion, we found that dietary Pi induces MFS2 expression. This results in the formation of Malpighian calcium-Pi stones, while RNAi-mediated knockdown of MFS2 increases blood (hemolymph) Pi and decreases formation of Malpighian tubule stones in flies cultured on high Pi medium. Conversely, microinjection of adults with the phosphaturic human hormone fibroblast growth factor 23 ( FGF23 ) induces tubule expression of MFS2 and decreases blood Pi. This action of FGF23 is blocked by genetic ablation of MFS2 . Furthermore, genetic overexpression of the fly FGF branchless (bnl) in the tubules induces expression of MFS2 and increases Malpighian tubule stones suggesting that bnl is the endogenous phosphaturic hormone in adult flies. Finally, genetic ablation of MFS2 increased fly life span, suggesting that Malpighian tubule stones are a key element whereby high Pi diet reduces fly longevity previously reported by us. In conclusion, MFS2 mediates excretion of Pi in Drosophila , which is as in higher species under the hormonal control of FGF-signaling .

Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging

“…Median lifespan increased to 49 ± 1.9 days and 47 ± 1.8 days, respectively, by inhibiting P i intake through the addition of either sevelamer (which blocks P i absorption) or PFA (which inhibits the cellular uptake of P i ) to the SM [ 361 ]. Finally, more recent findings show that PFA and the ablation of MFS2 (a P i transporter in fly Malphigian tubules that functions in P i excretion) increase blood P i , decrease the formation of Malphigian tubule calcium-P i stones, and increase lifespan in Drosophila [ 362 ]. These results suggest that the excretion of P i and the formation of Malpighian tubule stones reduce the longevity of flies cultured on a high P i medium [ 362 ].…”

“…Finally, more recent findings show that PFA and the ablation of MFS2 (a P i transporter in fly Malphigian tubules that functions in P i excretion) increase blood P i , decrease the formation of Malphigian tubule calcium-P i stones, and increase lifespan in Drosophila [ 362 ]. These results suggest that the excretion of P i and the formation of Malpighian tubule stones reduce the longevity of flies cultured on a high P i medium [ 362 ].…”

FGF23 signalling and physiology

“…Based on expression in the tubule and stimulation of MFS2 gene expression by dietary Pi and FGF23, MFS2 may function as an excretory Pi-transporter in the Malpighian tubules. This function is different from the situation in mammalian kidneys, where the type II sodium-dependent Pi co-transporters NPT2a and NPT2c help reclaim Pi from the urine and may reflect the unique anatomy of the fly renal system, which lacks a connection to a glomerulus as seen in higher species (Rose et al 2019), and absence of skeletal mineral stores for Pi. The roles of the FGF, FGFR, and KL orthologs in D. melanogaster in Pi homeostasis require further study, although in particular bnl may promote Pi excretion as transgenic overexpression of bnl increases MFS2 expression (Rose et al 2019).…”

“…Conversely, the gain of function in Egl-15 leads to fluid accumulation in the animal's pseudocoelom, hinting at the roles of FGF23 and KL in mineral excretion in higher species (Huang & Stern 2004). Likewise, D. melanogaster has three FGF orthologs, branchless (bnl), pyramus (pyr), and thisbe (ths); two FGFR orthologs, breathless (btl) and heartless (htl); and one KL ortholog (CG9701) which were identified through the DRSC integrative ortholog prediction tool (DIOPT) ( Table 1) (Rose et al 2019). As in humans, these FGFR orthologs signal via the MAPK pathway (Sen et al 2011).…”

“…We recently showed that flies microinjected with human FGF23 become hypophosphatemic. This hypophosphatemia appears to be due to upregulation of the type I sodiumdependent Pi co-transporter major facilitator superfamily 2 (MFS2) in their Malpighian tubules (Rose et al 2019). Ablation of MFS2 prevents this FGF23 effect and also blocks the formation of fly calcium Pi kidney stones.…”