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Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis.

Abstract

Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na(+)-dependent phosphate (Pi) uptake decreased by 50%-60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na(+)-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells.

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  • Authors+Show Affiliations

    ,

    Department of Molecular Nutrition Institution of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; and.

    , , , , , , , , , , ,

    Source

    MeSH

    Acrylamides
    Animals
    Hepatectomy
    Hypophosphatemia
    Kidney
    Male
    Mice
    Mice, Inbred C57BL
    NAD
    Niacinamide
    Nicotinamide Phosphoribosyltransferase
    Parathyroidectomy
    Piperidines
    Rats
    Rats, Wistar
    Sodium-Phosphate Cotransporter Proteins
    Sodium-Phosphate Cotransporter Proteins, Type IIa

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    24262791

    Citation

    Nomura, Kengo, et al. "Hepatectomy-related Hypophosphatemia: a Novel Phosphaturic Factor in the Liver-kidney Axis." Journal of the American Society of Nephrology : JASN, vol. 25, no. 4, 2014, pp. 761-72.
    Nomura K, Tatsumi S, Miyagawa A, et al. Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis. J Am Soc Nephrol. 2014;25(4):761-72.
    Nomura, K., Tatsumi, S., Miyagawa, A., Shiozaki, Y., Sasaki, S., Kaneko, I., ... Miyamoto, K. (2014). Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis. Journal of the American Society of Nephrology : JASN, 25(4), pp. 761-72. doi:10.1681/ASN.2013060569.
    Nomura K, et al. Hepatectomy-related Hypophosphatemia: a Novel Phosphaturic Factor in the Liver-kidney Axis. J Am Soc Nephrol. 2014;25(4):761-72. PubMed PMID: 24262791.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis. AU - Nomura,Kengo, AU - Tatsumi,Sawako, AU - Miyagawa,Atsumi, AU - Shiozaki,Yuji, AU - Sasaki,Shohei, AU - Kaneko,Ichiro, AU - Ito,Mikiko, AU - Kido,Shinsuke, AU - Segawa,Hiroko, AU - Sano,Mitsue, AU - Fukuwatari,Tsutomu, AU - Shibata,Katsumi, AU - Miyamoto,Ken-ichi, Y1 - 2013/11/21/ PY - 2013/11/23/entrez PY - 2013/11/23/pubmed PY - 2014/5/28/medline SP - 761 EP - 72 JF - Journal of the American Society of Nephrology : JASN JO - J. Am. Soc. Nephrol. VL - 25 IS - 4 N2 - Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na(+)-dependent phosphate (Pi) uptake decreased by 50%-60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na(+)-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells. SN - 1533-3450 UR - https://www.unboundmedicine.com/medline/citation/24262791/Hepatectomy-related_hypophosphatemia:_a_novel_phosphaturic_factor_in_the_liver-kidney_axis L2 - http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=24262791 DB - PRIME DP - Unbound Medicine ER -