Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice

Abstract

. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am J Physiol Renal Physiol 306: F833-F843, 2014. First published February 19, 2014 doi:10.1152/ajprenal.00133.2013.-The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/ SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of P i whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary P i, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney. phosphate homeostasis; epithelial transport; renal proximal tubules; SLC34 cotransporters INORGANIC PHOSPHATE (P I ) IS an essential anion that is required for a wide variety of molecular and cellular processes. In mammals, the concentration of P i in plasma remains within a relative tightly controlled range (0.8 -1.4 mM in humans). This control is executed by organs responsible for P i absorption/ excretion (intestine and kidneys), P i storage (bones), as well as production and secretion of regulatory factors (kidneys, bones, and parathyroid glands; for a review, see Ref. 5). However, the final control of P i homeostasis depends on the kidneys as they can adjust the urinary excretion of the anion to the body's specific requirements. The importance of the kidney in this process is highlighted by the deleterious consequences of both renal wasting and retention of the anion. Thus renal loss of P i leads primarily to skeletal deformities whereas hyperphosphatemia is implicated in vascular calcification and mortality in end-stage kidney disease (for a review, see Ref.2). The renal epithelia express at least three Na-dependent P i cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2 (for a review, see Ref. 14). These cotransporters are expressed in the brush-borde...

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

“…The occurrence of Fanconi syndrome in the context of SLC34A1 mutation is not clear. In two different mouse models of SLC34A1 deficiency due to genetic deletion or compound heterozygous mutations no signs of Fanconi syndrome have been observed [22]. Suggested explanations include a specific toxic tubular effect of this particular mutation due to intracellular accumulation or an additional mutation in this consanguineous family [23].…”

FGF23-Klotho signaling axis in the kidney

“…It has been shown in mice with a kidney-specific ablation of NaPi-2c that the phosphaturic action of FGF23 is mainly determined by downregulation of the apical membrane abundance of NaPi-2a, with NaPi-2c playing only a minor role [41]. In addition, the absence of renal NaPi-2c does not seem to be important for the control of phosphate homeostasis under physiological conditions in mice [41].…”

“…It has been shown in mice with a kidney-specific ablation of NaPi-2c that the phosphaturic action of FGF23 is mainly determined by downregulation of the apical membrane abundance of NaPi-2a, with NaPi-2c playing only a minor role [41]. In addition, the absence of renal NaPi-2c does not seem to be important for the control of phosphate homeostasis under physiological conditions in mice [41]. In contrast, humans with loss-of-function mutations in NaPi-2c are characterized by hypophosphatemia and renal phosphate wasting which obviously cannot be balanced by counter-regulatory changes in NaPi-2a [42].…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…For instance, Napi-2c is expressed more significantly during weaning in the rat. 27,29 1.5. Tumor-Induced Osteomalacia TIO, also known as oncogenic hypophosphatemic osteomalacia, is a rare disorder (paraneoplastic) of renal phosphate wasting.…”