Abstract: TH-PO028
TREM1/3 Deficiency Impairs Tissue Repair After AKI and Mitochondrial Metabolic Flexibility in Tubular Epithelial Cells
Session Information
- AKI: Mechanisms - Primary Injury and Repair - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Author
- Tammaro, Alessandra, Amsterdam UMC, Amsterdam, Netherlands
Background
Long-term sequelae of acute kidney injury (AKI) are associated with incomplete recovery of renal function and the development of chronic kidney disease (CKD), which can be due to a maladaptive repair characterized by aberrant innate immune activation, mitochondrial pathology and accumulation of senescent tubular epithelial cells (TECs). TREM-1 is an innate immune receptor expressed by inflammatory and epithelial cells, both players in renal repair after ischemia/reperfusion (IR)-induced AKI. Despite this, the role of TREM-1 in renal repair has never been investigated.
Methods
WT and TREM1/3 KO mice were subjected to different models of renal IR (severe and mild). Animals were sacrificed 1, 5 and 10 day after surgery. Blood was collected to determine renal function parameters. Kidneys were harvested for hystological examination, RNA isolation and protein determination. For ex-vivo studies, primary TECs were isolated from WT and TREM1/3 KO animals and exposed to hypoxia/re-oxygenation experiments. Seahorse analysis, metabolomics, senescence and wound healing assays were used as readout for in vitro studies.
Results
TREM1/3 KO mice displayed no major differences during the acute phase of injury, but increased mortality was observed in the recovery phase. This detrimental effect was associated with maladaptive repair, characterized by persistent tubular damage, inflammation, fibrosis,TEC senescence and metabolic reprogramming. In vitro, we observed an altered mitochondrial homeostasis and cellular metabolism in TREM1/3 KO TECs. This was associated with G2/M arrest and increased ROS accumulation. Further exposure of cells to ROS-generating triggers drove the cells into a stress-induced senescent state, which was partly reverted by treatment with a mitochondria anti-oxidant.
Conclusion
In summary, we have unraveled a novel (metabolic) mechanism by which TREM1/3 deficiency drives senescence in TECs. This involves redox imbalance, mitochondrial dysfunction and a decline in cellular metabolic activities. These finding suggest a novel role for TREM-1 in maintaining tubular homeostasis through regulation of mitochondrial metabolic flexibility. Finally, this study demonstrates a novel link between immunometabolism and tubular epithelial senescence.