Cloning, gene structure and dietary regulation of the type-IIc Na/Pi cotransporter in the mouse kidney

Abstract

We have demonstrated previously that the type-IIc Na/Pi cotransporter is a growth-related renal Na/Pi cotransporter that is highly expressed in kidney of the weaning rat. In the present study, we investigated type-IIc Na/Pi cotransporter function further by cloning the mouse gene and characterizing the corresponding protein. The mouse type-IIc transporter amino acid sequence shows a high degree of similarity to the human (86%) and rat (95%) type-IIc Na/Pi-cotransporters. The mouse gene contained 14 exons and mapped to chromosome 2. The DNA sequence upstream from exon 1 is GC rich. The upstream region does not contain an apparent TATA box, but does contain two dietary Pi-responsive elements, which are potential binding sites for the transcription factor micro E3 (TFE3). Microinjection of mouse type-IIc cRNA into Xenopus oocytes demonstrated sodium-dependent Pi cotransport activity. The affinity for Pi was about 200 microM in 100 mM Na. Feeding adult mice fed a low-Pi diet increased the expression of type-IIc protein in the apical membrane of renal proximal tubular cells. Hybrid depletion studies suggested that the type-IIc transporter contributes to about 30% of Na/Pi cotransport in the kidney of adult mice fed a low-Pi diet. The present study suggests that the type-IIc Na/Pi cotransporter is a functional of renal Pi transporter in adult mice fed a low-Pi diet.

Intestinal and renal adaptation to a low-Pi diet of type II NaPi cotransporters in vitamin D receptor- and 1αOHase-deficient mice

“…Another type II NaP i cotransporter, NaP i -IIc, was recently described and localized to the renal proximal tubules (21). The observed reduced urinary P i excretion of mice fed a high-P i diet may therefore be explained by a change in the content of the NaP i -IIc cotransporter.…”

“…In both organs, a low-P i diet provokes an increase in the abundance of apically located type II NaP i cotransporters: NaP i -IIa and NaP i -IIc in proximal tubules and NaP i -IIb in small intestine (12,16,21). The precise mechanisms of regulation are still not entirely clear.…”

The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels

“…This regulation occurs essentially by trafficking of the protein, lysosomal degradation, recruitment of newly synthesized transporters [5,26,[29][30] and may also include transcriptional regulation [34]. Much less is known about the regulation of NaPi-IIc being regulated also by PTH, FGF23, and Pi intake with a slower change in brush border membrane abundance upon high Pi intake or PTH application [8,28,[43][44]. Similarly, Pit-2 is regulated by PTH and dietary Pi or potassium intake but no further regulators have been identified to date [15,44,59].…”

Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters

“…The rats were kept on a low-phosphate diet (0.1% P i content) (Kliba AG, Switzerland) for 3 days to upregulate renal phosphate reabsorption in the BBM of all proximal tubular segments as described previously (3). The protein abundance of all three known phosphate transporters, NaPi-IIa, NaPi-IIc and Pit-2, are increased by low phosphate diets (26,33,35,36). Moreover, all rats received 4 % CaCl 2 in their drinking water 24 hrs prior to experiments to suppress endogenous PTH levels (3).…”