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

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

Research output: Contribution to journalArticle

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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, longchain 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.

Original languageEnglish (US)
Pages (from-to)1057-1068
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
StatePublished - Mar 3 2014

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Acyl Coenzyme A
Apoptosis
Atrophy
Fatty Acids
Caspase 2
Sodium-Hydrogen Antiporter
Albuminuria
Kidney Diseases
Phosphatidylinositols
Chronic Renal Insufficiency
Disease Progression
Tail
Albumins
Cell Survival
Kidney
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Khan, S., Jawdeh, B. G. A., Goel, M., Schilling, W. P., Parker, M. D., Puchowicz, M., ... Schelling, J. R. (2014). Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. Journal of Clinical Investigation, 124(3), 1057-1068. https://doi.org/10.1172/JCI71863

Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. / Khan, Shenaz; Jawdeh, Bassam G.Abu; Goel, Monu; Schilling, William P.; Parker, Mark D.; Puchowicz, Michelle; Yadav, Satya P.; Harris, Raymond C.; El-Meanawy, Ashraf; Hoshi, Malcolm; Shinlapawittayatorn, Krekwit; Deschênes, Isabelle; Ficker, Eckhard; Schelling, Jeffrey R.

In: Journal of Clinical Investigation, Vol. 124, No. 3, 03.03.2014, p. 1057-1068.

Research output: Contribution to journalArticle

Khan, S, Jawdeh, BGA, Goel, M, Schilling, WP, Parker, MD, Puchowicz, M, Yadav, SP, Harris, RC, El-Meanawy, A, Hoshi, M, Shinlapawittayatorn, K, Deschênes, I, Ficker, E & Schelling, JR 2014, 'Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis', Journal of Clinical Investigation, vol. 124, no. 3, pp. 1057-1068. https://doi.org/10.1172/JCI71863
Khan, Shenaz ; Jawdeh, Bassam G.Abu ; Goel, Monu ; Schilling, William P. ; Parker, Mark D. ; Puchowicz, Michelle ; Yadav, Satya P. ; Harris, Raymond C. ; El-Meanawy, Ashraf ; Hoshi, Malcolm ; Shinlapawittayatorn, Krekwit ; Deschênes, Isabelle ; Ficker, Eckhard ; Schelling, Jeffrey R. / Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 3. pp. 1057-1068.
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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, longchain 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.",
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AU - Khan, Shenaz

AU - Jawdeh, Bassam G.Abu

AU - Goel, Monu

AU - Schilling, William P.

AU - Parker, Mark D.

AU - Puchowicz, Michelle

AU - Yadav, Satya P.

AU - Harris, Raymond C.

AU - El-Meanawy, Ashraf

AU - Hoshi, Malcolm

AU - Shinlapawittayatorn, Krekwit

AU - Deschênes, Isabelle

AU - Ficker, Eckhard

AU - Schelling, Jeffrey R.

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N2 - 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, longchain 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.

AB - 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, longchain 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.

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