title: 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.
authors.affiliation: Department of Molecular Nutrition Institution of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; and.
authors.forename: Kengo
authors.initials: K
authors.lastname: Nomura
authors.forename: Sawako
authors.initials: S
authors.lastname: Tatsumi
authors.forename: Atsumi
authors.initials: A
authors.lastname: Miyagawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiozaki
authors.forename: Shohei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ito
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kido
authors.forename: Hiroko
authors.initials: H
authors.lastname: Segawa
authors.forename: Mitsue
authors.initials: M
authors.lastname: Sano
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fukuwatari
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shibata
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D006498:Hepatectomy / Q000009:adverse effects*; D017674:Hypophosphatemia / Q000209:etiology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000502:physiology; D016105:Parathyroidectomy; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D050608:Sodium-Phosphate Cotransporter Proteins / Q000502:physiology; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000502:physiology
chemical_list: D000178:Acrylamides; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D009243:NAD; D009536:Niacinamide; D054409:Nicotinamide Phosphoribosyltransferase