Effect of NAD+ boosting on kidney ischemia-reperfusion injury

• Published in: PloS one 2021-06, Vol.16 (6), p.e0252554-e0252554
• Main Authors: Morevati, Marya, Egstrand, Søren, Nordholm, Anders, Mace, Maria L., Andersen, Claus B., Salmani, Rouzbeh, Olgaard, Klaus, Lewin, Ewa
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; Biochemistry; Biology and Life Sciences; Bone morphogenetic protein 7; Cell death; Cell survival; Creatinine; Drafting software; Editing; Fibrosis; Forensic pathology; Forensic science; Funding; Homeostasis; Hospitals; Inflammation; Injury analysis; Ischemia; Kidneys; Klotho protein; Medicine and Health Sciences; Methodology; NAD; Nephrology; Pathology; Pathophysiology; Phagocytosis; Plasma; Reperfusion; Surgery; Transforming growth factor-b1; Visualization
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0252554

Acute kidney injury (AKI) is associated with a very high mortality and an increased risk for progression to chronic kidney disease (CKD). Ischemia-reperfusion injury (IRI) is a model for AKI, which results in tubular damage, dysfunction of the mitochondria and autophagy, and in decreased cellular nicotinamide adenine dinucleotide (NAD + ) with progressing fibrosis resulting in CKD. NAD + is a co-enzyme for several proteins, including the NAD + dependent sirtuins. NAD + augmentation, e.g. by use of its precursor nicotinamide riboside (NR), improves mitochondrial homeostasis and organismal metabolism in many species. In the present investigation the effects of prophylactic administration of NR on IRI-induced AKI were studied in the rat. Bilateral IRI reduced kidney tissue NAD + , caused tubular damage, reduced α-Klotho (klotho), and altered autophagy flux. AKI initiated progression to CKD, as shown by induced profibrotic Periostin ( postn ) and Inhibin subunit beta-A, ( activin A / Inhba ), both 24 hours and 14 days after surgery. NR restored tissue NAD + to that of the sham group, increased autophagy (reduced p62) and sirtuin1 ( Sirt1 ) but did not ameliorate renal tubular damage and profibrotic genes in the 24 hours and 14 days IRI models. AKI induced NAD + depletion and impaired autophagy, while augmentation of NAD + by NR restored tissue NAD + and increased autophagy, possibly serving as a protective response. However, prophylactic administration of NR did not ameliorate tubular damage of the IRI rats nor rescued the initiation of fibrosis in the long-term AKI to CKD model, which is a pivotal event in CKD pathogenesis.