In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LD) and lipotoxicity. Yet, it is unclear how these two effects correlate with each other in the kidney and how they are influenced by dietary patterns. By using a diabetes mouse model, we find here that high fat diet enriched in the monounsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTC) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). This effect was particularly evident S2/S3 but not S1 segments of the proximal tubule. Combining transcriptomics, lipidomics and functional studies, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. Mechanistically, ER stress is caused by elevated levels of saturated TAG precursors, reduced LD formation and, consequently, higher membrane order in the ER. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and by increasing both TAG and LD formation. Our study thus emphasizes the importance of monounsaturated fatty acids for the dietary management of DKD by preventing lipid bilayer stress in the ER and promoting TAG and LD formation in PTCs.
- iRECs lipidomic data have been deposited in Dryadhttps://doi.org/10.5061/dryad.x95x69pm1.- Kidney cortex of diabetic mice lipidomic data have been deposited in Dryadhttps://doi.org/10.5061/dryad.qv9s4mwgx.- iRECs Transcriptome raw data (bam files) can be found at https://www.ncbi.nlm.nih.gov/sra/PRJNA809508- iRECs Transcriptome processed data (FPKM and DEG) have been deposited in DryadDOI https://doi.org/10.5061/dryad.gqnk98sq7-The full code for the TF activity-lipid correlation analysis can be found in: https://github.com/saezlab/Albert_perez_RNA_lipid/tree/main/scripts
Data from: Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetesryad Digital Repository, doi:10.5061/dryad.x95x69pm1.
Data from: Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetesDryad Digital Repository, doi:10.5061/dryad.qv9s4mwgx.
Lipotoxicity in renal tubular epithelial cellsNCBI BioProject, PRJNA809508.
Data from: Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetesDryad Digital Repository, doi:10.5061/dryad.
- Jiayi Li
- Suresh Ramakrishnan
- Matias Simons
- Kelli Grand
- Soeren S Lienkamp
- Albert Pérez-Martí
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All of the experimental protocols in this study were performed with the approval of the animal experimentation ethics committee of the University Paris Descartes (CEEA 34), projects registered as 17-058 and 20-022
- Raymond Harris
© 2022, Pérez-Martí et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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