Abstract: SA-PO812
Renalase (RNLS) Attenuates Cisplatin (CP)-Induced CKD by diminishing Stress Kinases and Regulated Necrosis
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., Yale and VAMC, West Haven, Connecticut, United States
- Guo, Xiaojia, Yale Univ, Woodbridge, Connecticut, United States
- Chen, Tian-Min, Yale University, New Haven, Connecticut, United States
- Velazquez, Heino, Yale and VAMC, West Haven, Connecticut, United States
- Desir, Gary V., Yale and VAMC, West Haven, Connecticut, United States
Background
CP is widely used as an effective chemotherapeutic agent for cancer yet it causes CKD upon repeated doses, which limits its use. We have induced CKD in mice using 2 doses of CP 2 weeks apart and have shown that CKD developes 2 weeks after the second dose. Previously we have shown that RNLS attenuates acute ischemic and cisplatin-induced AKI. We now report on the role of RNLS to prevent CP-induced CKD.
Methods
CKD was induced by 2 doses of CP 15 mg/kg ip 2 weeks apart in C57BL/6J mice. Mouse PT cells (TKPTS) were incubated with 25 ug/ml CP and studied 24 hours after treatment. A non-enzymatic peptide of RNLS (p81), 4mg/kg sc, that signals via a surface receptor was given to a separate group of mice 3 times a week beginning with the first dose of CP. Immunoblotting, immunoflourescence, cell viability, and serum creatinine was applied to evaluate the effect of RNLS on cell viability, expression of stress kinases and regulated necrosis mediators, and renal function.
Results
RNLS expression was reduced in CP-induced CKD by 60% at 4 weeks and almost completely at 9 weeks in the proximal tubules of CKD mice. CP reduced renalase expression in TKPTS cells treated with CP as well. RNLS peptide p81 reduced CP-induced CKD signifcantly(n=4, p<.05) and reduced Kim-1, RIPK1, and MAPK activation. Viability of TKPTS cells was increased and activation of caspase 3 (apoptosis), TLR2, RIPK 1 and 3, and MLKL (necroptosis) was supressed. RNLS knockout animals had a heightened stress kinase and necroptotic response to CP.
Conclusion
We conclude that RNLS attenuates CP-induced CKD by intervening in cell death pathways activated by CP. RNLS acts as a survival factor for proximal tubule cells as RNLS knockout provokes cell death by similar pathways. These data suggest that RNLS may be an effective therapeutic agent to prevent CKD in patients treated with repeated doses of cisplatin.
Funding
- Other NIH Support