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Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Na+-coupled phosphate cotransporters from the SLC34 and SLC20 families of solute carriers mediate transepithelial transport of inorganic phosphate (Pi). NaPi-IIa/Slc34a1, NaPi-IIc/Slc34a3, and Pit-2/Slc20a2 are all expressed at the apical membrane of renal proximal tubules and therefore contribute to renal Pi reabsorption. Unlike NaPi-IIa and NaPi-IIc, which are rather kidney-specific, NaPi-IIb/Slc34a2 is expressed in several epithelial tissues, including the intestine, lung, testis, and mammary glands. Recently, the expression of NaPi-IIb was also reported in kidneys from rats fed on high Pi. Here, we systematically quantified the mRNA expression of SLC34 and SLC20 cotransporters in kidneys from mice, rats, and humans. In all three species, NaPi-IIa mRNA was by far the most abundant renal transcript. Low and comparable mRNA levels of the other four transporters, including NaPi-IIb, were detected in kidneys from rodents and humans. In mice, the renal expression of NaPi-IIa transcripts was restricted to the cortex, whereas NaPi-IIb mRNA was observed in medullary segments. Consistently, NaPi-IIb protein colocalized with uromodulin at the luminal membrane of thick ascending limbs of the loop of Henle segments. The abundance of NaPi-IIb transcripts in kidneys from mice was neither affected by dietary Pi, the absence of renal NaPi-IIc, nor the depletion of intestinal NaPi-IIb. In contrast, it was highly upregulated in a model of oxalate-induced kidney disease where all other SLC34 phosphate transporters were downregulated. Thus, NaPi-IIb may contribute to renal phosphate reabsorption, and its upregulation in kidney disease might promote hyperphosphatemia.

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Funding

This study was supported by a grant from the Swiss National Science Foundation to C.A.W (31003A-176125) and the National Center of Competence in Research NCCR Kidney.CH, Switzerland.

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  1. Sarah E. Motta and Pedro Henrique Imenez Silva contributed equally to this work.

Authors and Affiliations

  1. Institute of Physiology, Switzerland and National Center of Competence in Research NCCR Kidney, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland

    Sarah E. Motta, Pedro Henrique Imenez Silva, Arezoo Daryadel, Betül Haykir, Eva Maria Pastor-Arroyo, Carla Bettoni, Nati Hernando & Carsten A. Wagner

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  1. Sarah E. Motta
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Supplementary table 1 Sequence or source and efficiency of qPCR primers (Fw= forward; Rv= reverse) and probes used to quantify the expression of Slc20 and Slc34 cotransporters in samples from mice, rats and human. Supplementary Figure 1. Validation of the anti NaPi-IIb antibody A-D) Immunofluorescence of mouse ileum with an anti-NaPi-IIb antibody (green) as well as with DAPI (blue) and phalloidin (red). A, B) signal in the absence of the antigenic peptide. C, D) signal in the presence of the antigenic peptide. E-F) Westernblots on kidney homogenates (K) and intestinal BBM (I) of mice using anti-NaPi-IIb (top panels) and actin (bottom panels) antibodies. Signals E) without or F) with antigenic peptide. The arrowhead indicates the position of the transporter in BBM isolated from ileum. Figure 2. Intestinal mRNA expression of Na/Pi cotransporters: real-time PCR. Relative mRNA expression of NaPi-IIa, NaPi-IIb, NaPi-IIc, Pit-1 and Pit-2 in A) ileum of WT mice (n=5) as well as B) duodenum and C) jejunum from rats (n=5). Expression of Pit-1 in rat duodenum was not tested. Ct values of each mRNA were normalized to the Ct values of the control mRNA HPRT. Supplementary Figure 3. Effect of oxalate treatment on wild type mice A) Plasma creatinine, and B) plasma urea. n=6. ** p<0.01, *** p< 0.001. Student t-test.Supplementary Figure 4. Data from single cell transcriptome analysis from mouse kidneys A) Expression of NaPi-IIa, NaPi-IIb and NaPi-IIc mRNAs in juxtamedullary nephrons and ureteric epithelium. Scheme taken from Ransick et al; Developmental Cell, 2019. Average expressions are given in logarithmic scale. Subdivisions indicate: 1) podocytes (visceral epithelium), 2) parietal epithelium, 3) segment 1 of proximal tubule – female, 4) segment 1 of proximal tubule – male, 5) segment 2 of proximal tubule –female, 6) segment 2 of proximal tubule – male, 7) segment 3 of proximal tubule – female, 8) segment 3 of proximal tubule – male, 9A) LOH thin descending limb of inner stripe of outer medulla of cortical nephron, 9B) LOH thin descending limb of inner stripe of outer medulla of juxtamedullary nephron, 10) upper LOH thin descending limb of inner medulla of juxtamedullary nephron, 11) lower LOH thin descending limb of inner medulla of juxtamedullary nephron, 12) lower LOH thin limb of inner medulla of juxtamedullary nephron, 13) lower LOH thin limb of inner medulla of juxtamedullary nephron, 14) upper LOH thin ascending limb of inner medulla of juxtamedullary nephron, 15) distal straight tubule of inner stripe of outer medulla (syn: thick ascending limb of LOH), 16) distal straight tubule of outer stripe of outer medulla and cortex (syn: thick ascending limb of LOH), 17) macula densa, 18) distal convoluted tubule, 19) nephron connecting tubule, 20) principal-like cell of nephron connecting tubule, 21) intercalated type non-A non-B cell of nephron connecting tubule, 22) intercalated type A cell of nephron connecting tubule and cortical collecting duct, 23) principal-like cell of cortical collecting duct, 24) intercalated type B cell of cortical collecting duct, 25) intercalated type A cell of outer medullary collecting duct, 26) principal cell of outer medullary collecting duct, 27) intercalated type A cell of inner medullary collecting duct, 28) principal cell of inner medullary collecting duct type 1, 29) principal cell of inner medullary collecting duct type 2, 30) principal-like cell of deep inner medullary collecting duct type 1, 31) cell of deep inner medullary collecting duct type 2 and 32) deep medullary epithelium of pelvis. B) Expression of NaPi-IIa, NaPi-IIb, NaPi-IIc, Pit-1 and Pit-2 mRNAs in kidneys from mice. Data extracted from Park et al. Science 2018. (PPTX 1635 kb)

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Motta, S.E., Imenez Silva, P.H., Daryadel, A. et al. Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease. Pflugers Arch - Eur J Physiol 472, 449–460 (2020). https://doi.org/10.1007/s00424-020-02370-9

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