Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury
العنوان: | Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury |
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المؤلفون: | Marcello Polesel, Andrew M. Hall, Joana Raquel Martins, Susan Ghazi, Milica Bugarski |
المساهمون: | University of Zurich |
المصدر: | J Am Soc Nephrol |
بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2021. |
سنة النشر: | 2021 |
مصطلحات موضوعية: | Male, medicine.medical_specialty, Kidney Cortex, 10017 Institute of Anatomy, Bicarbonate, 030232 urology & nephrology, 610 Medicine & health, Mice, 03 medical and health sciences, chemistry.chemical_compound, Oxygen Consumption, 0302 clinical medicine, Internal medicine, medicine, Animals, 10035 Clinic for Nephrology, 030304 developmental biology, Acidosis, 0303 health sciences, Kidney, urogenital system, Acute kidney injury, Metabolic acidosis, Lipid metabolism, General Medicine, Acute Kidney Injury, Lipid Metabolism, NAD, medicine.disease, Mitochondria, Mice, Inbred C57BL, Glutamine, Disease Models, Animal, Kidney Tubules, Basic Research, medicine.anatomical_structure, Endocrinology, chemistry, Nephrology, 570 Life sciences, biology, NAD+ kinase, 10024 Center for Microscopy and Image Analysis, medicine.symptom |
الوصف: | BACKGROUND: The kidney plays an important role in maintaining normal blood pH. Metabolic acidosis (MA) upregulates the pathway that mitochondria in the proximal tubule (PT) use to produce ammonia and bicarbonate from glutamine, and is associated with AKI. However, the extent to which MA causes AKI, and thus whether treating MA would be beneficial, is unclear. METHODS: Gavage with ammonium chloride induced acute MA. Multiphoton imaging of mitochondria (NADH/membrane potential) and transport function (dextran/albumin uptake), oxygen consumption rate (OCR) measurements in isolated tubules, histologic analysis, and electron microscopy in fixed tissue, and urinary biomarkers (KIM-1/clara cell 16) assessed tubular cell structure and function in mouse kidney cortex. RESULTS: MA induces an acute change in NAD redox state (toward oxidation) in PT mitochondria, without changing the mitochondrial energization state. This change is associated with a switch toward complex I activity and decreased maximal OCR, and a major alteration in normal lipid metabolism, resulting in marked lipid accumulation in PTs and the formation of large multilamellar bodies. These changes, in turn, lead to acute tubular damage and a severe defect in solute uptake. Increasing blood pH with intravenous bicarbonate substantially improves tubular function, whereas preinjection with the NAD precursor nicotinamide (NAM) is highly protective. CONCLUSIONS. MA induces AKI via changes in PT NAD and lipid metabolism, which can be reversed or prevented by treatment strategies that are viable in humans. These findings might also help to explain why MA accelerates decline in function in CKD. |
وصف الملف: | JASN-2020-07-1003.R2_Proof_hi.pdf - application/pdf |
تدمد: | 1533-3450 1046-6673 |
الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::55e5489349120ba488ea12d2a262f9baTest https://doi.org/10.1681/asn.2020071003Test |
حقوق: | OPEN |
رقم الانضمام: | edsair.doi.dedup.....55e5489349120ba488ea12d2a262f9ba |
قاعدة البيانات: | OpenAIRE |
تدمد: | 15333450 10466673 |
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