Kidney Week

Abstract: SA-PO112

Depletion of Salvage NAD+ Biosynthesis Exerts Opposing Effects in Inflamed Proximal Tubule vs. Microvascular Endothelium

Session Information

• AKI: Metabolism and Cell Death
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Etzrodt, Valerie, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Valerie Etzrodt, MD

• Chen, Liping, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Liping Chen, MS

• Clark, Amanda J., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Amanda J. Clark, MD

• Vu, Kyle Q., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Kyle Q. Vu

• Saade, Marie Christelle, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Marie Christelle Saade, MD

• Parikh, Samir M., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Samir M. Parikh, MD, FASN

Background

Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD+) synthesizing salvage pathway. NAMPT’s roles in the kidney, particularly in proximal tubule cells and adjacent microvascular endothelial cells, are of significant interest due to their vital functions in maintaining renal homeostasis. We hypothesized that NAMPT enzymatic function is necessary for renal tubular resilience to injury whereas its effects in the endothelium may be dispensable given the low metabolic activity of the latter.

Methods

In vivo disease models: LPS 17.5 mg/kgBW; in vitro models: human proximal tubule kidney cells (HK2), human umbilical vein EC (HUVECs), transendothelial electrical resistance, NAD(H) biochemical assessments.

Results

In a murine model of systemic inflammation, total kidney NAMPT was upregulated. This effect appeared to localize to ECs. HUVECs treated with inflammatory stimuli confirmed dose-dependent induction of NAMPT expression along with canonical markers of vascular inflammation such as intercellular adhesion molecular 1 (ICAM-1). In contrast, HK2 cells exhibited no induction of NAMPT following exposure to inflammatory stimuli. As expected, knockdown or pharmacological inhibition of NAMPT in HK2 cells depleted intracellular NAD+ and exacerbated the expression of kidney injury markers following inflammation. In contrast, knockdown or pharmacological inhibition of NAMPT in inflamed HUVECs significantly attenuated expression of ICAM-1. Interestingly, reintroduction of β-nicotinamide mononucleotide, in NAMPT deficient HUVECs abrogated the anti-inflammatory effect.

Conclusion

Kidney endothelial NAMPT may be markedly induced during systemic inflammation. Whereas NAMPT’s major role in the renal tubule may be promote NAD+ homeostasis, NAMPT in the endothelium may be a potent regulator of vascular inflammation. Future studies have to clarify how NAMPT can be cell-specifically targeted in acute inflammation.

Funding

• NIDDK Support