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

J Am Soc Nephrol. 2021 Feb;32(2):342-356. doi: 10.1681/ASN.2020071003. Epub 2021 Jan 21.


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.

Keywords: acidosis; acute renal failure; metabolism; mitochondria; proximal tubule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis / etiology*
  • Acidosis / metabolism
  • Acidosis / pathology
  • Acute Kidney Injury / etiology*
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Animals
  • Disease Models, Animal
  • Kidney Cortex / metabolism
  • Kidney Cortex / pathology
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology*
  • Lipid Metabolism / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • NAD / metabolism*
  • Oxygen Consumption / physiology


  • NAD