Abstract: FR-PO170
Altered Lipid Metabolism Exacerbates Endotoxin-Associated Kidney Injury in Diabetes
Session Information
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- De Luca, Thomas, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Janosevic, Danielle, Indiana University School of Medicine, Indianapolis, Indiana, United States
Background
Diabetes is a risk factor for endotoxin-associated acute kidney injury (sAKI). In a non-comorbid murine model of sAKI, we previously identified that renal tissue plays a role in the mediation of innate immune responses and cell-specific temporal changes in the lipid metabolism transcriptome, culminating in organ failure (16 hr) followed by recovery (24 hr). Bioactive lipids (bL) are spatially and functionally dysregulated in both diabetes and sepsis and play diverse roles in immunity, inflammation, and kidney injury, with ceramide at the nexus of sphingolipid metabolism. We hypothesized that metabolic dysregulation of bL mediates sAKI in the diabetic milieu.
Methods
Lipopolysaccharide (LPS) was given intravenously (iv) to diabetic (BKS.Cg-Dock7m+/+ Leprdb/J) mice (db) and littermates (db+) sacrificed at 0 (baseline), 16 (injury), 24 hr (recovery) after LPS iv, serum, kidneys collected. Serum creatinine (Scr) quantified (MS). ScRNAseq: dissociated kidneys sequenced (10x Chromium) and clustered (Seurat). Cryogel mounted tissue (15 uM) imaged and untargeted DESI-MSI and analysis performed (positive and negative ion modes, m/z range: 100-1,200, Cardinal MSI), attributions assigned (Lipid Maps Structural Database and Human Metabolome Database).
Results
Db at 24 hr (vs. 0 hr) had persistent renal injury (Kim1 Log2FC 8.32±1.01, Scr 0.38±0.34) vs. db+ (Kim1 Log2FC 3.51± 0.58, Scr (0.10 ± 0.01). In db (vs db+), putative C16 ceramide remained elevated in the renal medulla (16, 24 hr), reduced levels of protective C24 ceramide in the cortex (0 hr). In db (0-24 hrs) there was significantly altered metabolism of glycerophospholipids (i.e., phosphoinositols), fatty acyls, sterols, compared to db+. Db scRNAseq at 16,24 hrs had decreased expression in glycosphingolipid-metabolic enzymes (Glb1) in proximal tubule and similar changes in ceramide synthases (e.g., Cers 1-6), sphingosine 1-phosphate receptors involved in sAKI inflammatory and immune responses.
Conclusion
We identified several classes of deregulated lipids and altered transcriptomic expression of associated enzymes in db mice which exhibited persistent renal injury. This may lead to the deregulation of cellular function and thus, maladaptive recovery from sAKI in db. Additional work to identify ions/genes of interest and their similarities with the human metabolome will be necessary to determine causality.
Funding
- Private Foundation Support