Anna Faivre1, Elena Katsyuba2, Thomas Verissimo1, Maja Lindenmeyer3, Renuga Devi Rajaram1, Maarten Naesens4, Carolyn Heckenmeyer1, Adrienne Mottis2, Eric Feraille1, Pietro Cippà5, Clemens Cohen6, Alban Longchamp7, Florent Allagnat7, Joseph M Rutkowski8, David Legouis1,9, Johan Auwerx2, Sophie de Seigneux1,10. 1. Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. 2. Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 3. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium. 5. Division of Nephrology, Regional Hospital of Lugano, Lugano, Switzerland. 6. Nephrological Center, Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany. 7. Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. 8. Department of Medical Physiology, Texas A&M University Health Science Center, Bryan, TX, USA. 9. Intensive Care Unit, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland. 10. Service of Nephrology, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland.
Abstract
BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI). METHODS: We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia-reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models. RESULTS: RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI. CONCLUSION: Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.
BACKGROUND:Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI). METHODS: We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia-reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models. RESULTS: RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI. CONCLUSION: Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.
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Authors: Thomas Verissimo; Anna Faivre; Anna Rinaldi; Maja Lindenmeyer; Vasiliki Delitsikou; Christelle Veyrat-Durebex; Carolyn Heckenmeyer; Marylise Fernandez; Lena Berchtold; Delal Dalga; Clemens Cohen; Maarten Naesens; Sven-Erik Ricksten; Pierre-Yves Martin; Jérôme Pugin; Franck Merlier; Karsten Haupt; Joseph M Rutkowski; Solange Moll; Pietro E Cippà; David Legouis; Sophie de Seigneux Journal: J Am Soc Nephrol Date: 2022-03-10 Impact factor: 14.978
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