Abstract: TH-PO881
Mitochondrial Dysfunction in FOXD1 Lineage Cells Has a Key Role in the Development of Anemia Associated with CKD
Session Information
- Anemia and Iron Metabolism
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Anemia and Iron Metabolism
- 200 Anemia and Iron Metabolism
Authors
- Kobayashi, Hanako, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Haase, Volker H., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Anemia is one of the common complications of chronic kidney disease (CKD) diminishing quality of life and increasing cardiovascular mobility and mortality in affected patients. Inadequate production of renal erythropoietin (EPO) is the main cause of CKD-associated anemia. EPO is produced in perivascular fibroblast-like cells which are derived from FOXD1 lineage cells and are regulated by hypoxia-inducible factor-2 (HIF-2). Despite recent advances in understanding EPO regulation, the mechanisms for the loss of EPO production are ill-defined. Perivascular fibroblast-like cells are viewed as quiescent; however, they can rapidly proliferate, migrate, and produce extracellular matrix in kidney disease. The role of metabolic regulation in this process is only incompletely understood. Mitochondria (mt) are essential for cellular metabolism, and mt dysfunction is a common feature of acute and chronic kidney diseases. However, the function of mt in perivascular fibroblast-like cells is largely unknown.
Methods
To investigate mt function in renal stroma, we generated and analyzed mice with interstitial cell-specific deficiency of mt transcription factor A (TFAM) using FoxD1-cre transgenic mice (FoxD1-Tfam-/-). TFAM is required for the transcription of mt genes and mt DNA replication and is thus essential for the maintenance of mt mass and function.
Results
We demonstrate that suppression of mt mass in renal stroma results in progressive renal failure, characterized by elevated BUN, tubulointerstitial fibrosis, and glomerulosclerosis. Single cell RNA sequencing of FoxD1-Tfam-/- interstitial cells demonstrated increased expression of genes involved in amino acid metabolism and ATF4-mediated stress responses. Furthermore, FoxD1-Tfam-/- mice developed anemia, characterized by relative EPO deficiency in response to hypoxia or treatment with HIF stabilizing agents. This was due to the inability to stabilize HIF-2α in Tfam-/- stroma.
Conclusion
In summary, we have developed a novel genetic mouse model of slowly progressive CKD-associated anemia that mimics human disease. Our data suggest that mt in renal stroma play a critical role for the maintenance of normal kidney function and homeostasis.
Funding
- NIDDK Support