RENAL ADAPTATION TO PHOSPHATE DEPRIVATION - LESSONS FROM THE X-LINKEDHYP MOUSE

The X-linked Hyp mutation, a murine homologue of X-linked hypophosphat emia in humans, is characterized by renal defects in phosphate reabsor ption and vitamin D metabolism. In addition, the renal adaptive respon se to phosphate deprivation in mutant Hyp mice differs from that of no rmal littermates. While Hyp mice fed a low phosphate diet retain the c apacity to exhibit a significant increase in renal brush-border membra ne sodium-phosphate cotransport in vitro, the mutants fail to show an adaptive increase in maximal tubular reabsorption of phosphate per vol ume of glomerular filtrate (TmP/GFR) in vivo. Moreover, unlike their n ormal counterparts, Hyp mice respond to phosphate restriction with a f all in the serum concentration of 1,25-dihydroxyvitamin D [1,25(OH)2D] that can be ascribed to increased renal 1,25(OH)2D catabolism. The di ssociation between the adaptive brush-border membrane phosphate transp ort response and the TmP/GFR and vitamin D responses observed in Hyp m ice is also apparent in X-linked Gy mice and hypophysectomized rats. B ased on these findings and the notion that transport across the brush- border membrane reflects proximal tubular function, we suggest that th e adaptive TmP/GFR response requires the participation of 1,25(OH)2D o r a related metabolite and that a more distal segment of the nephron i s the likely target for the 1,25(OH)2D-dependent increase in overall t ubular phosphate conservation.