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Basic Research
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Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury

Milica Bugarski, Susan Ghazi, Marcello Polesel, Joana R. Martins and Andrew M. Hall
JASN February 2021, 32 (2) 342-356; DOI: https://doi.org/10.1681/ASN.2020071003
Milica Bugarski
1Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Susan Ghazi
1Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Marcello Polesel
1Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Joana R. Martins
1Institute of Anatomy, University of Zurich, Zurich, Switzerland
2Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland
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Andrew M. Hall
1Institute of Anatomy, University of Zurich, Zurich, Switzerland
3Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
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Significance Statement

Clinical studies have suggested that metabolic acidosis (MA) aggravates tubular damage in patients with both AKI and CKD, but the mechanisms were unknown. Intravital live cell imaging and other complementary techniques demonstrated in the mouse kidney that MA induces acute changes in the mitochondrial NAD redox state, respiratory chain function, and lipid metabolism, which collectively lead to tubular cell damage. Intravenous injection of bicarbonate increases blood pH and improves tubular function, whereas pretreatment with an NAD precursor is highly protective. Thus, changes in cell metabolism explain the harmful effects of MA on kidney tubules, which therapeutic strategies that are viable in humans can substantially ameliorate.

Abstract

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.

  • acidosis
  • acute renal failure
  • metabolism
  • mitochondria
  • proximal tubule
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (2)
Journal of the American Society of Nephrology
Vol. 32, Issue 2
February 2021
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Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury
Milica Bugarski, Susan Ghazi, Marcello Polesel, Joana R. Martins, Andrew M. Hall
JASN Feb 2021, 32 (2) 342-356; DOI: 10.1681/ASN.2020071003

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Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury
Milica Bugarski, Susan Ghazi, Marcello Polesel, Joana R. Martins, Andrew M. Hall
JASN Feb 2021, 32 (2) 342-356; DOI: 10.1681/ASN.2020071003
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More in this TOC Section

  • Targeted Single-Cell RNA-seq Identifies Minority Cell Types of Kidney Distal Nephron
  • A Comprehensive Map of mRNAs and Their Isoforms across All 14 Renal Tubule Segments of Mouse
  • Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney
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Keywords

  • acidosis
  • acute renal failure
  • metabolism
  • mitochondria
  • proximal tubule

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