Effect of NAD+ boosting on kidney ischemia-reperfusion injury

Morevati, Marya; Egstrand, Søren; Nordholm, Anders; Mace, Maria L; Andersen, Claus B; Salmani, Rouzbeh; Ølgaard, Klaus; Lewin, Ewa

doi:10.1371/journal.pone.0252554

Cited by 24 publications

(20 citation statements)

References 102 publications

(125 reference statements)

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“…To our knowledge, this is the first time the beneficial effects of the addition of NADH to NMP preparations have been shown. Since the molecular maladaptations we observed, as well as the morphological changes, are in line with findings in acute kidney injury (AKI), and the molecular improvement with addition of NAD has also been described for AKI in vivo (Arykbaeva et al, 2021) (Faivre et al, 2021;Morevati et al, 2021) (Morevati et al, 2021), KSI could additionally be a model well suited to study drug treatment for the acute phases of ischemic AKI. Other ex-vivo techniques for the study of ischemia-reperfusion (e.g., cell culture microflow chamber) take comparable approaches (Giraud et al, 2020).…”

Section: Discussionsupporting

confidence: 84%

A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

et al. 2022

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Kidney transplantation is the only definitive therapy for end-stage kidney disease. The shortage of organs for transplantation is the main limitation of this life-saving treatment. Normothermic machine perfusion (NMP) is a novel preservation technique with the potential to increase the number of transplantable kidneys through reducing delayed graft function and organ evaluation under physiological conditions. To date, the cellular effects and possible pharmacological interventions during machine perfusion are incompletely understood. A major limitation is the technically complex, time-consuming, and small-scale replication of NMP in rodent models. To overcome this, we developed a 3D-printed, high throughput ex-vivo mouse kidney slice incubator (KSI) mimicking mouse kidney NMP by working under closely resembling conditions. KSI significantly reduced the time per experiment and increased the sample throughput (theoretical: 54 incubations with n = 500/day). The model recapitulated the cellular responses during NMP, namely increased endoplasmic reticulum stress (ER stress). Using KSI, five pharmacological interventions against ER stress taken from the literature were tested. While four were ineffective and excluded, one, β-Nicotinamide-adenine-dinucleotide (NADH), ameliorated ER stress significantly during KSI. The test of NADH in mouse kidney NMP replicated the positive effects against ER stress. This suggests that testing the addition of NADH during clinical kidney NMP might be warranted.

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Section: Discussionsupporting

confidence: 84%

A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

et al. 2022

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“…In addition, administered 14 days before bilateral IRI, NR (500 mg/kg/day, i.p.) did not improve renal tubular damage and profibrotic genes expression at Day 14 after IRI [170].…”

Section: Preclinical Studiesmentioning

confidence: 77%

NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

Chanvillard

Tammaro

Sorrentino

2022

Cells

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Premature aging causes morphological and functional changes in the kidney, leading to chronic kidney disease (CKD). CKD is a global public health issue with far-reaching consequences, including cardio-vascular complications, increased frailty, shortened lifespan and a heightened risk of kidney failure. Dialysis or transplantation are lifesaving therapies, but they can also be debilitating. Currently, no cure is available for CKD, despite ongoing efforts to identify clinical biomarkers of premature renal aging and molecular pathways of disease progression. Kidney proximal tubular epithelial cells (PTECs) have high energy demand, and disruption of their energy homeostasis has been linked to the progression of kidney disease. Consequently, metabolic reprogramming of PTECs is gaining interest as a therapeutic tool. Preclinical and clinical evidence is emerging that NAD+ homeostasis, crucial for PTECs’ oxidative metabolism, is impaired in CKD, and administration of dietary NAD+ precursors could have a prophylactic role against age-related kidney disease. This review describes the biology of NAD+ in the kidney, including its precursors and cellular roles, and discusses the importance of NAD+ homeostasis for renal health. Furthermore, we provide a comprehensive summary of preclinical and clinical studies aimed at increasing NAD+ levels in premature renal aging and CKD.

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“…Protein analysis was performed using standard methods (Supplemental Methods). ( 37 ) Primary antibodies: 1:5000 total β‐catenin (detects C‐terminal region of β‐catenin; 610153; BD Biosciences, Franklin Lakes, NJ, USA), 1:1000 active β‐catenin (detects nonphosphorylated β‐catenin at Ser37 and Thr41; 05‐665; Merck Millipore, Burlington, MA, USA), 1:1000 osteopontin (ab8448; Abcam, Cambridge, UK). Park7 (ab18257; Abcam) was used as reference protein.…”

Section: Methodsmentioning

confidence: 99%

The Calcified Vasculature in Chronic Kidney Disease Secretes Factors that Inhibit Bone Mineralization

et al. 2022

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Vascular calcification and bone disorder progress simultaneously in chronic kidney disease (CKD). Still, how the complex pathological mechanisms are linked is only sparsely understood. Up to now, the focus has been on the disturbed bone metabolism in developing vascular calcification. However, our group has recently demonstrated that vascular calcification has negative effects on bone formation and mineralization as shown in the bone of normal recipient rats transplanted with the calcified aorta from CKD rats. In the present in vitro study, the hypothesis of a direct crosstalk between the vasculature and bone was examined. Calcified aortas from 5/6 nephrectomized rats and normal aortas from control rats were excised and incubated ex vivo. The calcified aorta secreted large amounts of sclerostin, dickkopf‐1 (Dkk1), and activin A. Both normal and calcified aortas secreted frizzle‐related protein 4 (SFRP4). Aorta rings were co‐incubated with the osteoblast‐like cell line UMR‐106. The calcified aorta strongly inhibited calcium crystal formation in UMR‐106 cells, together with a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog (ANKH). The strong stimulation of osteopontin was blocked by lithium chloride, indicating involvement of Wnt/β‐catenin signaling. The present in vitro study shows detrimental effects of the calcified aorta on bone cell mineralization. These findings support the hypothesis of an active role of the calcified vasculature in the systemic CKD–mineral and bone disorder (CKD‐MBD), resulting in a pathological vascular–bone tissue crosstalk. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Effect of NAD+ boosting on kidney ischemia-reperfusion injury

Cited by 24 publications

References 102 publications

A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

The Calcified Vasculature in Chronic Kidney Disease Secretes Factors that Inhibit Bone Mineralization

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