2. Academic Validation
  3. Activation of nicotinamide phosphoribosyltransferase protects against unilateral renal ischemia-reperfusion injury via the NAD+/SIRT1/PGC-1α signaling pathway and modulation of NFκB/TNF-α/IL-6

Activation of nicotinamide phosphoribosyltransferase protects against unilateral renal ischemia-reperfusion injury via the NAD+/SIRT1/PGC-1α signaling pathway and modulation of NFκB/TNF-α/IL-6

  • Eur J Pharm Sci. 2025 Sep 29:214:107302. doi: 10.1016/j.ejps.2025.107302.
Elsayed A Elmorsy 1,  Mostafa M Khodeir 2,  Manal M Kamal 3,  Mohamed El-Sayed 4,  Mariam S Alharbi 5,  Hamad Alsaykhan 6,  Rabab S Hamad 7,  Mustafa Ahmed Abdel-Reheim 8,  Hanan Eissa 9,  Attia M Gabr 10,  Mohamed F Hindawy 11,  Mohamed R Abdel-Hamed 12,  Maha M Amer 13,  Amel Ahmed 14,  Alshaimaa A Farrag 15,  Ahmed Kaid Alantry 16,  Basem H Elesawy 17,  Abdel-Rahman Youssef 18,  Ahmed Sameh 19,  Sameh Saber 20
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia; Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: a.almarsa@qu.edu.sa.
  • 2 Department of Pathology, College of Medicine, Qassim University, Qassim, Buraidah 51452, Saudi Arabia; Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt. Electronic address: mm.khodeir@qu.edu.sa.
  • 3 Department of Physiology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia; Department of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt. Electronic address: manalkamal@aun.edu.eg.
  • 4 Faculty of Medicine, Horus University, New Damietta 34518, Egypt. Electronic address: 7211024@horus.edu.eg.
  • 5 Department of Medicine, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia. Electronic address: 24426@qu.edu.sa.
  • 6 Department of Anatomy and Histology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia. Electronic address: h.alsaykhan@qu.edu.sa.
  • 7 Biological Sciences Department, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia. Electronic address: rhamad@kfu.edu.sa.
  • 8 Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia. Electronic address: m.ahmed@su.edu.sa.
  • 9 Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: hibrahim@ub.edu.sa.
  • 10 Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia. Electronic address: amsalm@qu.edu.sa.
  • 11 Department of Anatomy and Histology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia. Electronic address: mhndaoy@qu.edu.sa.
  • 12 Department of Anatomy and Histology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Electronic address: m.younes@qu.edu.sa.
  • 13 Department of Anatomy and Histology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Electronic address: m.amer@qu.edu.sa.
  • 14 Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address: amel.ahmed@aun.edu.eg.
  • 15 Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt. Electronic address: alshaima@aun.edu.eg.
  • 16 Department of Physiology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia. Electronic address: ak.alantry@qu.edu.sa.
  • 17 Department of Pathology, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia; Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: belesawy@tu.edu.sa.
  • 18 Department of Basic and Clinical Oral Sciences, Division of Basic Medical Sciences, College of Dental Medicine, Umm Al-Qura University, Makkah, Saudi Arabia. Electronic address: amyoussef@uqu.edu.sa.
  • 19 Faculty of Computing and Information Sciences, Egypt University of Informatics, Cairo, Egypt; Faculty of Computing and Information Sciences, University of Minnesota, Twin Cities, USA. Electronic address: sameh002@umn.edu.
  • 20 Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: sameh.saber@deltauniv.edu.eg.
PMID: 41033563 DOI: 10.1016/j.ejps.2025.107302
Abstract

Renal ischemia is a common cause of acute kidney injury (AKI), particularly in critical care settings, and remains a major challenge in nephrology due to the lack of effective therapeutic options. In AKI, there is an overstimulation of NAD+-consuming Enzymes leading to NAD+ depletion. To help replenish cellular NAD+ stores, this study explores for the first time the therapeutic potential of activating nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD+ salvage pathway, in a rat model of unilateral renal ischemia-reperfusion injury (IRI). Our findings demonstrate that SBI797812 (SBI)-induced NAMPT activation significantly improves renal function post-IRI, primarily through the NAD+/SIRT1/PGC-1α signaling pathway. NAMPT activation resulted in significant improvement in kidney function, including restored urine flow rate, reduced creatinine and blood urea nitrogen (BUN) levels, and decreased kidney injury biomarkers such as KIM-1 and NGAL. Additionally, SBI led to a reduction in inflammatory markers (NFκB, TNF-α and IL-6), oxidative stress markers, and Caspase-3, indicating enhanced renal protection. Western blot analysis further revealed upregulation of key mitochondrial biogenesis markers, including SIRT1, PGC-1α, and TFAM, highlighting the link between NAD+ restoration and improved mitochondrial function. In contrast, the inhibition of NAMPT with FK866 exacerbates injury, as indicated by worsened histological features, increased inflammation, and tubular necrosis, confirming the crucial role of NAMPT in mitigating ischemic damage. Considering the importance of NAD metabolism in mitochondrial function and cellular resiliency to tissue injury, these results underscore NAMPT activation as a promising therapeutic strategy for renal IRI, offering new insights for the management of ischemic AKI.

Keywords

Inflammation; NAMPT/NAD(+); NFκB/TNF-α/IL-6; Renal ischemia-reperfusion injury; SIRT1/PGC-1α/Nrf1/TFAM.

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