Abstract
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.
Highlights
Acute kidney injury (AKI) is a common syndrome affecting 5–7% of all hospitalized patients [1]
Our results show that the kidney Ischemia-reperfusion injury (IRI) already after 24 hours caused a pro-fibrotic shift in the pattern of expression of kidney genes and that the expression levels of the pro-fibrotic genes (Tgf-β1, Inhba and Periostin) 14 days after IRI were still significantly elevated in both nicotinamide riboside (NR) and vehicle rats, indicating that NAD+ boosting did not protect against transition from AKI to chronic kidney fibrosis in IRI rat model
The present model of acute kidney ischemia-reperfusion injury (IRI) is a model for AKI that resulted in a rapid decrease in kidney function with a significant increase in plasma urea and creatinine as well as in disturbed ion homeostasis leading to abnormal calcium levels after 24 hours
Summary
Acute kidney injury (AKI) is a common syndrome affecting 5–7% of all hospitalized patients [1]. It is associated with a significant increase in the length of hospital stay, in a very high mortality and often increased risk for progression to chronic kidney disease (CKD) and development of end-stage renal disease (ESRD) [2,3,4,5]. Ischemia-reperfusion injury (IRI) of the kidney is a leading cause of clinical AKI, which frequently occurs in patients with sepsis, patients subjected to major surgery. The pathophysiology of IRI includes tubular epithelial cell injury, endothelial injury, tubular cell death by apoptosis and necrosis signaling, inflammation, production of reactive oxygen species (ROS), and activation of autophagy [13,14,15]. A decline in antioxidants such as catalase (Cat), mitochondrial super-oxidase dismutase 2 (SOD2), and glutathione peroxidase might contribute to the pathophysiology of IRI [22]
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