Abstract: SA-PO813
Failed Repair, Not Fibrosis, Determines the Conversion of AKI to CKD in Cisplatin (CP)-Induced CKD
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Safirstein, Robert L., Connecticutt VAMC, West Haven, Connecticut, United States
- Landau, Sarah, Yale University School of Medicine, New Haven, Connecticut, United States
- Guo, Xiaojia, Yale Univ, Woodbridge, Connecticut, United States
- Velazquez, Heino, Yale and VAMC, West Haven, Connecticut, United States
- Torres, Richard, Yale University School of Medicine, New Haven, Connecticut, United States
- Moeckel, Gilbert W., Yale University School of Medicine, New Haven, Connecticut, United States
- Chang, John Jae Young, Connecticutt VAMC, West Haven, Connecticut, United States
- Desir, Gary V., Yale University School of Medicine, New Haven, Connecticut, United States
Background
Repeated doses of CP leads to CKD in humans but its mechanism is unknown. Previously we reported on a model of CP-induced CKD in mice that fully recapitulates the human disease.
Methods
Mice received CP 15mg/kg (ip) 2 weeks apart and multiphoton microscopy, cDNA microarray, PCR, western blotting, and immunocytochemistry were applied 4 weeks after the first dose in the two-dose model, when CKD is fully developed, and compared in mice 2 and 4 weeks after a single dose, when recovery is completed. Statistically significant differences (p<.05) were determined after correction for multiple comparisons.
Results
A fixed decline in GFR occured at 4 weeks in the 2 dose group and was associated with a loss of the glomerular parietal epithelial cells, a lesion that develops in CP-CKD. No increase in collagen deposition, the invasion of macrophages, or the loss of endothelial cells accompanied these changes. The onset of CKD showed expression of genes underlying regulated necrosis including Toll-Like Receptors 2 and 4, the Receptor-Interacting Protein Kinases 1 and 3, the Mixed Lineage Kinase-Like, and Cyclophilin D, while apoptosis played a minor role in cell death. Expression of the damage molecules Kim-1 and Ngal persisted after the second dose as did the reactivation of the stress kinases JNK and ERK, indicating continued injury. Cell cycle activity was markedly reduced after the second dose of CP. Although levels of CXCL1, CCL2, and CCR2 that play a critical role in CP AKI were elevated,. knockout of these genes did not prevent the development of CKD. Prominent and prolonged expression of the p21 gene was observed, which underlies the progression of CKD after 5/6 nephrectomy, but p21 knockout animals still progressed to CKD in the model.
Conclusion
Epithelial cell loss and regulated necrosis is a primary event in the development of CKD induced by two doses of CP. Progression of CKD is independent of the accumulation of fibrous tissue, macrophages, the loss of endothelial cells, or the production of key cytokines activated in AKI. Rather, deficient repair and continued loss of proximal tubule cells is the primary event in the conversion of AKI to CKD after repeated doses of cisplatin. A focus on interceding in the mechanisms of regulated necrosis could be successful in preventing CKD
Funding
- Other NIH Support