Abstract: SA-OR96
Changes in Gene Expression in Fatty Acid Metabolism and De Novo Lipogenesis Are Conserved in Human CKD and Animal Models
Session Information
- Glomerular Diseases: From Multiomics to Mechanisms
November 04, 2023 | Location: Room 103, Pennsylvania Convention Center
Abstract Time: 05:42 PM - 05:51 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
Authors
- Lee, Lauren Elizabeth, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Doke, Tomohito, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Mukhi, Dhanunjay, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Zeng, Li, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Background
Lipid accumulation has been consistently observed in kidneys of patients and animal models of kidney disease. Altered fatty acid oxidation (FAO) and de novo lipogenesis (DNL) signaling are proposed to drive the fatty kidney’s transition to kidney disease. However, changes in lipid composition and mechanisms of lipid accumulation that specifically drive alterations in FAO, DNL, and lipid uptake have not yet been characterized in unbiased manner.
Methods
We collected control (healthy) and diseased (diabetic and hypertensive kidney disease) human kidney samples from surgical nephrectomies. Demographics, clinical information, and estimated Glomerular Filtration Rate (eGFR) were collected, and histological analysis was performed by our renal pathologist. We analyzed gene expression changes in 405 microdissected human kidney tubule samples by RNA sequencing (RNA-seq). Bulk RNA-seq data from 3 mouse induced CKD models–unilateral ureteral obstruction (UUO, n=3), folic-acid induced nephropathy (FAN, n=3), and tubule-specific deletion of mitochondrial transcription factor A (TFAM, Ksp-Cre/Tfamflox/flox, n=3)–was generated. Furthermore, an unbiased metabolomics analysis was performed on both human and mouse kidney samples using the Metabolon platform.
Results
Kidney metabolomics data indicated complex changes in lipid levels. We observed accumulation of glycerophospholipids in diseased kidney samples. Transcripts related to FAO (ACOX1, ACOX2, CPT1, CPT2, ESRRA, FABP, HADHA, HADHB, PGC1a, PPARa, SLC25A20) were lower in kidneys of mouse CKD models. Their expression levels positively correlated with kidney fibrosis and negatively correlated with eGFR. Genes associated with DNL genes (ACSS2, ChREBP, SCAP) showed higher expression in mouse kidney disease models; their expression levels negatively correlated with fibrosis and slightly positively correlated with eGFR.
Conclusion
Unbiased metabolomics and gene expression analysis of human and mouse kidneys indicated increased lipid accumulation in diseased kidneys. Decrease in FAO and to some degree an increase in DNL likely contribute to lipid accumulation.
Funding
- NIDDK Support – Regeneron, Gilead, Novo Nordisk, Genentech, Novartis Boehringer Ingelheim, Bayer, Ventus, Variant Bio, Maze