title: 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
authors: S
authors: Khan
authors: Bassam G
authors: BG
authors: Abu Jawdeh
authors: Monu
authors: M
authors: Goel
authors: William P
authors: WP
authors: Schilling
authors: Mark D
authors: MD
authors: Parker
authors: Michelle A
authors: MA
authors: Puchowicz
authors: Satya P
authors: SP
authors: Yadav
authors: Raymond C
authors: RC
authors: Harris
authors: Ashraf
authors: A
authors: El-Meanawy
authors: Malcolm
authors: M
authors: Hoshi
authors: Krekwit
authors: K
authors: Shinlapawittayatorn
authors: Isabelle
authors: I
authors: Deschênes
authors: Eckhard
authors: E
authors: Ficker
authors: Jeffrey R
authors: JR
authors: Schelling
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001667:Binding, Competitive; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000473:pathology; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D027682:Cation Transport Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse