Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2014-03, Vol.124 (3), p.1057-1068

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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.