ArticleThe Journal of clinical investigation2014
Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 65 citations in OpenAlex.
- Apical proximal tubule fatty acid uptake-generated ceramides cause endoplasmic reticulum stress from altered membrane fluidity.JCI insight · 2026Article
- Allogeneic mesenchymal stromal cells ameliorate lupus nephritis by regulating lipid metabolism via ASGR1.Stem cell research & therapy · 2026Article
- Knockout of PI4-Kinase A in GnRH Neurons Causes their Prepubertal Death.bioRxiv : the preprint server for biology · 2026Article
- PI4-kinase A is essential for survival of the GnRH neurons.Frontiers in endocrinology · 2026Article
- Crosstalk between glomeruli and tubules.Nature reviews. Nephrology · 2025Review
- Astragaloside IV Improves Diabetic Kidney Disease by Regulating NLRP3 Inflammasome.Journal of diabetes research · 2025Review
- Article
- Altered lipid metabolism promoting cardiac fibrosis is mediated by CD34Experimental & molecular medicine · 2024Article
- Identification of Lipotoxicity-Related Biomarkers in Diabetic Nephropathy Based on Bioinformatic Analysis.Journal of diabetes research · 2024Article
- Tubulointerstitial injury in proteinuric chronic kidney diseases.Frontiers in medicine · 2024Review
- Definition of fatty acid transport protein-2 (FATP2) structure facilitates identification of small molecule inhibitors for the treatment of diabetic complications.International journal of biological macromolecules · 2023Article
- Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis.Nature communications · 2023Article
- Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms.Frontiers in endocrinology · 2023Review
- Review
- Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications.Physiological reviews · 2022Review
- PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease.Molecular medicine (Cambridge, Mass.) · 2022Article
- Glucose- and Non-Glucose-Induced Mitochondrial Dysfunction in Diabetic Kidney Disease.Biomolecules · 2022Review
- Ventricular arrhythmias in mouse models of diabetic kidney disease.Scientific reports · 2021Article
- KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease.Cell metabolism · 2021Article
- CT features of feline lipiduria and renal cortical lipid deposition.Journal of feline medicine and surgery · 2021Article
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14 authors at 3 institutions in 1 country.
Funding
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.
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