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: Kengo Nomura, Sawako Tatsumi, Atsumi Miyagawa, Yuji Shiozaki, Shohei Sasaki, Ichiro Kaneko, Mikiko Ito, Shinsuke Kido, Hiroko Segawa, Mitsue Sano, Tsutomu Fukuwatari, Katsumi Shibata, Ken-ichi Miyamoto
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 25 Issue 4 Pg. 761-72 (Apr 2014) ISSN: 1533-3450 [Electronic] United States
• PMID: 24262791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
• Piperidines
• Sodium-Phosphate Cotransporter Proteins
• Sodium-Phosphate Cotransporter Proteins, Type IIa
• NAD
• Niacinamide
• Nicotinamide Phosphoribosyltransferase

Topics

• Acrylamides (pharmacology)
• Animals
• Hepatectomy (adverse effects)
• Hypophosphatemia (etiology)
• Kidney (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NAD (metabolism)
• Niacinamide (metabolism)
• Nicotinamide Phosphoribosyltransferase (physiology)
• Parathyroidectomy
• Piperidines (pharmacology)
• Rats
• Rats, Wistar
• Sodium-Phosphate Cotransporter Proteins (physiology)
• Sodium-Phosphate Cotransporter Proteins, Type IIa (physiology)