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Kidney Week

Abstract: FR-PO134

Mitochondrial-Driven Inflammation in Aged Kidneys Is Exacerbated by Nicotinamide Mononucleotide but Ameliorated by Elamipretide

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Saleh, Tara A., University of Washington, Seattle, Washington, United States
  • Whitson, Jeremy A., High Point University, High Point, North Carolina, United States
  • Rabinovitch, Peter S., University of Washington, Seattle, Washington, United States
  • Sweetwyne, Mariya T., University of Washington, Seattle, Washington, United States
Background

Mitochondrial dysfunction is characterized by loss of structural integrity, decreased efficiency of the electron transport chain and is linked to cellular senescence and inflammation. With age, kidneys show progressive mitochondrial dysfunction, suggesting a therapeutic target to reduce aging kidney decline. Previously, systematic treatment of old mice with tetrapeptide, Elamipretide (ELAM), which interacts with the inner mitochondrial membrane to improve cristae structure and function, reduced mito-dysfunction and senescence in kidney and heart. We hypothesized that added intervention with Nicotinamide Mononucleotide (NMN), an NAD+ precursor, which contributes to the efficiency of ATP generation, would enhance the mito-energetic capability, thus decreasing mito-dysfunction and senescence in aged kidneys.

Methods

Old male mice were treated for 8 weeks at 24 months-old (mo) with: ELAM (osmotic pump, 3mg/kg), NMN (drinking water, 300 mg/kg), or ELAM+NMN combined. Untreated control mice were 4 mo (young) and 26 mo (old). Treated kidneys were harvested at 26 mo and preserved as frozen and formalin fixed tissues. Liver was analyzed to clarify intervention responses as global vs. kidney-specific mechanisms.

Results

Contrary to our hypothesis, NMN was detrimental in aged kidney by increasing mRNA expression of inflammatory cytokine, IL1b, relative to aged control kidneys (23-fold vs. 9-fold normalized to young, p=0.0002). RNA in situ hybridization showed IL1b expression localized to the old NMN-treated proximal tubules. In NMN treated kidneys IL-1β downstream targets CCL2, an inflammatory chemokine, and proximal tubule injury marker, KIM-1, were significantly upregulated. This was reduced in mice treated with combined ELAM+NMN. Finally, kidney F4/80+ macrophages by immunohistochemistry were higher in NMN treated mice, relative to old control or combined treatment groups. Il1b-driven inflammation was not observed in livers of NMN treated mice, demonstrating kidney specificity.

Conclusion

This suggests that high doses of NMN supplementation exacerbates existing inflammation pathways in aged kidneys but that this is reduced by ELAM mitochondrial intervention. Further work seeks to track NMN metabolite levels in primary tubule cells to better understand NMN-induced injury and ELAM protection in aged kidneys.

Funding

  • Other NIH Support