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Kidney Week

Abstract: SA-PO506

Increased Expression of NMN Transporter in the Kidneys in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Yasuda, Itaru, Keio University, Tokyo, Japan
  • Hasegawa, Kazuhiro, Keio University, Tokyo, Japan
  • Ono, Takashi, Shionogi & Co., Ltd, Osaka, Japan
  • Wakino, Shu, Keio University, Tokyo, Japan
  • Itoh, Hiroshi, Keio University, Tokyo, Japan
Background

In diabetic nephropathy (DN) and aging kidney, renal tissue concentration of nicotinamide adenine dinucleotide (NAD+) decreased, which is associated with renal dysfunction and albuminuria. The regulatory systems of NAD+ and its precursor, nicotinamide mononucleotide (NMN) are considered to play a crucial role in the maintenance of tissue NAD+ levels and the pathogenesis of DN. Recent study identified novel NMN transporter, Solute Carrier Family 12 Member 8 (Slc12a8). However, the role and location of NMN transporter in the kidneys as well as diabetic kidney remain unclear.

Methods

Type 2 diabetic db/db and control db/m mice were given regular chow diet ad libitum and euthanized at 24 weeks of age. We performed immunohistochemistry (IHC) of renal Slc12a8. Further, we measured serum and urinary NAD+ metabolites at 24 weeks of age. We evaluated renal NAD+ loss by calculating urine NAD+ to creatinine ratio (NAD+/Cr). NMN resorption was evaluated by the calculation of the fractional excretion of NMN (FeNMN).

Results

Tissue concentration of NAD+ decreased in db/db mice as compared to that in db/m mice at the age of 8 weeks, although that of NMN was not different. Urine NAD+/Cr ratios were higher in db/db mice than in db/m mice, suggesting an increased renal loss of NAD+ in db/db mice. IHC revealed weak staining of Slc12a8 in the glomerulus and proximal tubules, while strong staining in the distal tubules. Slc12a8 expression was higher in db/db mice than in db/m mice. While the expression of Slc12a8 was detected mostly on the basolateral side in db/m mice, it was expressed on both apical and basolateral side in db/db mice. These findings suggested the increased translocation of Slc12a8 towards apical side of distal tubular cells in DN. Consistently, FeNMN was lower in db/db mice than that in db/m mice, indicating increased resorption NMN at the tubules in db/db mice.

Conclusion

Novel NMN transporter, Slc12a8 was dominantly expressed in the distal tubules. In DN, Slc12a8 translocation to apical side was enhanced, which can be the compensatory mechanism for NAD+ loss in diabetic mice.