Preservation of vasculature is beneficial in mitigating cisplatin induced acute kidney injury

Abstract

Abstract Introduction Cisplatin, discovered over 50 years ago, is still one of the most potent anti-cancer chemotherapy drugs and broadly used in first-line chemotherapy regimens subscribed to about 10 to 20% of total cancer patients. However, the full anti-cancer potential of cisplatin remains underutilized due to treatment induced toxicities, particularly nephrotoxicity. A signal cisplatin dose in the range of 50–100 mg/m2 results in nephrotoxicity in about 30% of the patients and 50–70% of the patients receiving 5-day consecutive cisplatin at 15–20 mg/m2/day developed nephrotoxicity. Therefore, nephrotoxicity is a particularly limiting factor for cancer patients to remain in the effective treatment due to the acute kidney injury (AKI). Moreover, patients recovered from acute kidney injury from supportive measures have a 25% increase in risk of developing chronic kidney disease and a 50% increase in 10-year mortality risk. Purpose Although cisplatin induced AKI is well recognized, the role of vasculature damage in cisplatin induced AKI remains to be explored. Accordingly, this study is focused on evaluating the role of vasculature preservation in cisplatin induced AKI. Methods Cisplatin induced AKI mouse model was generated by i.p. injecting 30 mg/kg cisplatin to C57BL/6 mice. Saline injection was served as control (n=3 per group). To evaluate blood vessel damage induced by cisplatin, mice were sacrificed 24 and 48 hours post injection. DyLight 488 labeled Lectin (Cat#: DL-1174, Vector Laboratories, Burlingame, CA) was injected at dose of 2 ml/kg 10 minutes before the sacrifice. To mitigate cisplatin induced AKI, rapamycin PFC nanoparticles at 1 ml/kg were i.v. injected 24 hours before cisplatin injection (n=10 per group). Realtime in vivo visualization on blood vessel damage was achieved by using intravital microscopy on the mesenteric microcirculation with regard to fluorescence PFC nanoparticle extravasation (i.v. injected right before the visualization) and then intestine was excised for fluorescence microscopic evaluation. Results As demonstrated in Figure 1A–C, cisplatin induced vascular injury happened no later than 24 hours post cisplatin injection and worsened at 48 hours (less green fluorescence). As shown in Figure 1D, all the mice received 1 ml/kg rapamycin PFC nanoparticles were survived 48 hours post cisplatin injection. However, only 60% of the mice survived at 48 hours in the group with saline injection (n=10 per group). The rapamycin PFC nanoparticles treatment resulted in better vascular preservation, therefore there is less fluorescence PFC nanoparticle (∼220 nm) extravasation shown less red signaling in Figure 1E, comparing Figure 1F. Western blot results suggested enhanced autophagy and attenuated inflammation through mTOR signaling could be the underlying therapeutic mechanism of rapamycin PFC nanoparticles (Figure 1G). Conclusions Preservation of vasculature could be beneficial in reducing cisplatin induced acute kidney injury. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): NIH