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Renal dendritic cells ameliorate nephrotoxic acute kidney injury
Raghu K Tadagavadi1, W Brian Reeves
1Department of Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, PA, USA.
Abstract:
Inflammation contributes to the pathogenesis of acute kidney injury. Dendritic cells (DCs) are immune sentinels with the ability to induce immunity or tolerance, but whether they mediate acute kidney injury is unknown. Here, we studied the distribution of DCs within the kidney and the role of DCs in cisplatin-induced acute kidney injury using a mouse model in which DCs express both green fluorescence protein and the diphtheria toxin receptor. DCs were present throughout the tubulointerstitium but not in glomeruli. We used diphtheria toxin to deplete DCs to study their functional significance in cisplatin nephrotoxicity. Mice depleted of DCs before or coincident with cisplatin treatment but not at later stages experienced more severe renal dysfunction, tubular injury, neutrophil infiltration and greater mortality than nondepleted mice. We used bone marrow chimeric mice to confirm that the depletion of CD11c-expressing hematopoietic cells was responsible for the enhanced renal injury. Finally, mixed bone marrow chimeras demonstrated that the worsening of cisplatin nephrotoxicity in DC-depleted mice was not a result of the dying or dead DCs themselves. After cisplatin treatment, expression of MHC class II decreased and expression of inducible co-stimulator ligand increased on renal DCs. These data demonstrate that resident DCs reduce cisplatin nephrotoxicity and its associated inflammation.
Insights
Resident dendritic cells (DCs) protect against acute kidney injury. Depleting DCs worsened cisplatin-induced kidney damage and mortality, indicating their protective role in acute kidney injury.
Area of Science:
- Immunology
- Nephrology
- Cell Biology
Background:
- Inflammation is a key factor in acute kidney injury (AKI).
- Dendritic cells (DCs) are crucial immune cells, but their role in AKI is not well understood.
- Understanding DC function in AKI is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the distribution of dendritic cells (DCs) in the kidney.
- To determine the role of DCs in cisplatin-induced acute kidney injury (AKI).
- To elucidate the mechanisms by which DCs influence AKI pathogenesis.
Main Methods:
- Utilized a mouse model with fluorescently labeled DCs expressing diphtheria toxin receptors.
- Administered diphtheria toxin to deplete DCs and assessed kidney function and injury markers.
- Employed bone marrow chimeric mice to confirm cell-specific effects and rule out DC death as a factor.
- Analyzed DC surface marker expression (MHC class II, ICOS-ligand) post-cisplatin treatment.
Main Results:
- Dendritic cells (DCs) were found in the kidney tubulointerstitium, not glomeruli.
- DC depletion before or during cisplatin treatment led to increased renal dysfunction, tubular injury, and mortality.
- Enhanced injury in DC-depleted mice was attributed to CD11c-expressing hematopoietic cells, not dying DCs.
- Cisplatin treatment altered DC phenotype, decreasing MHC class II and increasing ICOS-ligand expression.
Conclusions:
- Resident dendritic cells (DCs) play a protective role in mitigating cisplatin-induced acute kidney injury (AKI).
- DCs reduce AKI severity and associated inflammation, highlighting their therapeutic potential.
- DC function and phenotype modulation are critical in the context of nephrotoxicity.
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