Kidney-Targeted Renalase Agonist Prevents Cisplatin-Induced Chronic Kidney Disease by Inhibiting Regulated Necrosis and Inflammation

Xiaojia Guo; Leyuan Xu; Heino Velazquez; Tian-Min Chen; Ryan M. Williams; Daniel A. Heller; Barbara Burtness; Robert Safirstein; Gary V. Desir

doi:10.1681/ASN.2021040439

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Significance Statement

Cisplatin is an effective chemotherapeutic agent for multiple solid tumors but its nephrotoxicity limits its clinical use. In this study in a mouse model, the researchers deliver an agonist peptide derived from renalase (RNLS), a secreted protein that enhances cell replication and decreases inflammation, specifically to the proximal tubule, the site of maximum renal damage induced by cisplatin. They provide evidence that this targeted delivery of the peptide (via encapsulation in mesoscale nanoparticles) protected against the development of cisplatin-mediated CKD, and that RNLS acts by inhibiting both regulated cell death and the proinflammatory state of CKD. These findings suggest that such an approach might provide a way to mitigate the nephrotoxicity of cisplatin and thus broaden its therapeutic efficacy in otherwise sensitive tumors.

Abstract

Background Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI.

Methods To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy.

Results In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment.

Conclusions Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.

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