NAD+激酶
谷氨酰胺
急性肾损伤
酸中毒
碳酸氢盐
脂质代谢
内科学
内分泌学
代谢性酸中毒
肾
医学
肾皮质
线粒体
新陈代谢
生物化学
化学
生物
酶
氨基酸
作者
Milica Bugarski,Susan Ghazi,Marcello Polesel,Joana Raquel Martins,Andrew M. Hall
出处
期刊:Journal of The American Society of Nephrology
日期:2021-01-21
卷期号:32 (2): 342-356
被引量:37
标识
DOI:10.1681/asn.2020071003
摘要
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.
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