Faculty Collaboration Database

Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. J Clin Invest 2014 Mar;124(3):1057-68

Date

02/18/2014

Pubmed ID

24531551

Pubmed Central ID

PMC3934167

DOI

10.1172/JCI71863

Scopus ID

2-s2.0-84896766836 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

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.

Author List

Khan S, Abu Jawdeh BG, Goel M, Schilling WP, Parker MD, Puchowicz MA, Yadav SP, Harris RC, El-Meanawy A, Hoshi M, Shinlapawittayatorn K, Deschênes I, Ficker E, Schelling JR

Author

Ashraf El-Meanawy MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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