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Abstract: TH-PO191

Nicotinamide Riboside Ameliorates a Depressive Phenotype in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Dial, Katelyn, Georgetown University, Washington, District of Columbia, United States
  • Myakala, Komuraiah, Georgetown University, Washington, District of Columbia, United States
  • Wang, Xiaoxin, Georgetown University, Washington, District of Columbia, United States
  • Jones, Bryce A., Georgetown University, Washington, District of Columbia, United States
  • Rodriguez, Olga C., Georgetown University, Washington, District of Columbia, United States
  • Harris, Brent T., Georgetown University, Washington, District of Columbia, United States
  • Albanese, Chris, Georgetown University, Washington, District of Columbia, United States
  • Levi, Moshe, Georgetown University, Washington, District of Columbia, United States

Group or Team Name

  • Levi Lab
Background

Diabetic kidney disease (DKD) is a risk factor for depression. Decreased NAD+ is correlated with the pathogenesis of DKD, and nicotinamide riboside (NR) supplementation restores kidney function in DKD. However, NR has never been investigated in models of DKD for its potential in treating the depressive phenotype.

Methods

Ten week-old db/m or db/db mice were administered 500 mg/kg NR either in the diet or drinking water for 20 weeks. At 18 weeks of treatment, mice underwent single-voxel 1H-MR-Spectroscopy (MRS) and behavioral evaluation such as the Open Field Test (OFT) and assessment of nesting behavior. After euthanasia, PAS staining, MALDI-guided SpatialOMx, IHC, ELISA, RT-qPCR and Western Blot analysis were performed on the mouse brain and kidneys.

Results

PAS staining showed mesangial expansion in db/db mouse kidneys, which was reduced with NR treatment. Urinary KIM-1 and albumin were increased in db/db mice and reduced with NR. NAD+ levels were significantly decreased in the brain frontal cortex (FC) of db/db mice compared to control mice, and NR treatment restored NAD+ levels to normal levels. db/db mice exhibited anxiety behavior in the OFT and built significantly less quality nests compared to db/m mice. Interestingly, NR significantly improved db/db mouse behavior in the OFT. MALDI showed reductions in FC N-acetylaspartate, lysophosphatidylcholine and adenosine monophosphate, and increases in FC and hippocampal (HPC) taurine and lysophosphatidylethanolamine in db/db mice compared to db/m. MRS of the FC showed increases in the relative concentrations of taurine, myoinositol and glutamate to glutamine ratio in db/db mice compared to db/m. NR treatment of db/db mice reduced hippocampal expression of Iba1, GFAP, and STING and FC expression of MCP1. In addition, p-GSK3B and PGC1a protein levels were significantly increased in the HPC of db/db mice and reduced by NR treatment.

Conclusion

Improvements in kidney function with NR treatment coincided with improvements in depressive behavior, reduced brain inflammation, enhanced expression of mitochondrial regulators, and changes in brain metabolites in the FC and HPC. This suggests that NR has potential benefits in the treatment of depression comorbid to DKD.

Funding

  • NIDDK Support