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.