Kidney Week

Abstract: FR-PO0343

Multi-Omic Integration Uncovers Sex-Specific Rewiring of NAD+ Metabolism and Signaling in AKI

Session Information

• AKI: Mechanisms - Metabolism and Repair
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Prasad, Praveena, The Pennsylvania State University, University Park, Pennsylvania, United States

Praveena Prasad, MS

• Sadler, Jaedon, The Pennsylvania State University, University Park, Pennsylvania, United States

Jaedon Sadler

• Diven, Garret S., The Pennsylvania State University, University Park, Pennsylvania, United States

Garret S. Diven

• Lizanne, Blanca, The Pennsylvania State University, University Park, Pennsylvania, United States

Blanca Lizanne

• Mansour, Mariam, The Pennsylvania State University, University Park, Pennsylvania, United States

Mariam Mansour

• McReynolds, Melanie R., The Pennsylvania State University, University Park, Pennsylvania, United States

Melanie R. McReynolds, MS, PhD

Background

Acute Kidney Injury (AKI) represents a global health crisis, affecting over 850 million individuals with a notably higher prevalence in females. Despite its high disease burden-impacting about 1 in 5 people globally, there are currently no effective treatments, only limited supportive care. A classic hallmark of AKI is the disruption of Nicotinamide Adenine Dinucleotide (NAD⁺) homeostasis- a critical redox co-factor and co-substrate for key regulatory enzymes such as sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38. While renal NAD⁺ depletion is well-documented in ischemic and toxic AKI, it remains unclear whether this deficit stems from impaired biosynthesis, accelerated consumption, or a systemic imbalance in metabolite flux. We hypothesized that AKI-induced NAD⁺ depletion is driven by sex-specific dysregulation of synthesis pathways, alongside augmented enzymatic consumption.

Methods

Using a Cisplatin-induced AKI mouse model, we performed systemic metabolic profiling via stable isotope tracing. Mice were infused with [2,4,5,6-²H₄] nicotinamide (NAM) and [U-¹³C] tryptophan (Trp), followed by liquid chromatography-mass spectrometry (LC-MS) to quantify steady-state metabolite concentrations and whole-body NAD⁺ turnover rates.

Results

Our data demonstrates that AKI induces systemic multi-organ disruption of NAD⁺ metabolism. We observed an accumulation of the toxic catabolites N-Me-6PY and N-Me-4PY, signaling an imbalance in NAM homeostasis. NAM isotope tracing revealed a male-specific impairment of NAD⁺ production via the salvage pathway in the spleen, which was remarkably preserved in females. Tryptophan tracing showed increased [M+6] NAD⁺ enrichment in the livers of both sexes. However, AKI females exhibited significantly higher [M+6] NAM levels across the kidney, liver, and spleen, suggesting a compensatory mechanism where NAM is synthesized and released into circulation to offset salvage disruption. Transcriptomic analysis identified a female-specific upregulation of NAD⁺-consuming enzymes in the injured kidney, potentially driving the decline in renal NAD⁺ levels despite increased systemic flux.

Conclusion

Collectively, these findings demonstrate that AKI fundamentally rewires NAD⁺ bioenergetics in a sex-distinct manner, underscoring the critical need for sex-stratified therapeutic strategies aimed at normalizing metabolic flux to restore renal function.