Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis

J Clin Invest. 2014 Mar;124(3):1057-68. doi: 10.1172/JCI71863. Epub 2014 Feb 17.


Chronic kidney disease progression can be predicted based on the degree of tubular atrophy, which is the result of proximal tubule apoptosis. The Na+/H+ exchanger NHE1 regulates proximal tubule cell survival through interaction with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], but pathophysiologic triggers for NHE1 inactivation are unknown. Because glomerular injury permits proximal tubule luminal exposure and reabsorption of fatty acid/albumin complexes, we hypothesized that accumulation of amphipathic, long-chain acyl-CoA (LC-CoA) metabolites stimulates lipoapoptosis by competing with the structurally similar PI(4,5)P2 for NHE1 binding. Kidneys from mouse models of progressive, albuminuric kidney disease exhibited increased fatty acids, LC-CoAs, and caspase-2-dependent proximal tubule lipoapoptosis. LC-CoAs and the cytosolic domain of NHE1 directly interacted, with an affinity comparable to that of the PI(4,5)P2-NHE1 interaction, and competing LC-CoAs disrupted binding of the NHE1 cytosolic tail to PI(4,5)P2. Inhibition of LC-CoA catabolism reduced NHE1 activity and enhanced apoptosis, whereas inhibition of proximal tubule LC-CoA generation preserved NHE1 activity and protected against apoptosis. Our data indicate that albuminuria/lipiduria enhances lipotoxin delivery to the proximal tubule and accumulation of LC-CoAs contributes to tubular atrophy by severing the NHE1-PI(4,5)P2 interaction, thereby lowering the apoptotic threshold. Furthermore, these data suggest that NHE1 functions as a metabolic sensor for lipotoxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Animals
  • Apoptosis*
  • Binding, Competitive
  • Cation Transport Proteins / chemistry
  • Cation Transport Proteins / metabolism*
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / pathology
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Tubules, Proximal / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Nitric Oxide Synthase Type III / deficiency
  • Nitric Oxide Synthase Type III / genetics
  • Phosphatidylinositol 4,5-Diphosphate / chemistry
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Protein Binding
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / pathology
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers / chemistry
  • Sodium-Hydrogen Exchangers / metabolism*


  • Acyl Coenzyme A
  • Cation Transport Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Slc9a1 protein, mouse
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse