Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis
Shenaz Khan, … , Eckhard Ficker, Jeffrey R. Schelling
Shenaz Khan, … , Eckhard Ficker, Jeffrey R. Schelling
Published February 17, 2014
Citation Information: J Clin Invest. 2014;124(3):1057-1068. https://doi.org/10.1172/JCI71863.
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Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis

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.

Authors

Shenaz Khan, Bassam G. Abu Jawdeh, Monu Goel, William P. Schilling, Mark D. Parker, Michelle A. Puchowicz, Satya P. Yadav, Raymond C. Harris, Ashraf El-Meanawy, Malcolm Hoshi, Krekwit Shinlapawittayatorn, Isabelle Deschênes, Eckhard Ficker, Jeffrey R. Schelling

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Figure 3

Low-affinity binding between LC-CoAs and the cNHE1.

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Low-affinity binding between LC-CoAs and the cNHE1. LC-CoA binding to NH...
LC-CoA binding to NHE1 was determined by SPR, using immobilized NHE1 cytosolic domain (cNHE1) peptide as ligand and LC-CoAs as analytes, as described in Methods. (A) SPR sensorgrams for palmitoyl-CoA (Kd = 3.4 ± 0.9 × 10–5 M; n = 3). (B) SPR sensorgrams for oleoyl-CoA (Kd = 2.3 ± 0.3 × 10–5 M; n = 3). (C) SPR sensorgrams for palmitoyl-CoA at a range of pH values.