Background Repeated administration of cisplatin causes chronic kidney disease (CKD). In previous studies, we reported that the kidney-secreted survival protein renalase and an agonist peptide protected mice from cisplatin-induced acute kidney injury.
Methods To investigate whether kidney-targeted delivery of renalase might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a renalase agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of renalase, single-cell RNA sequencing (RNA-seq) analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma renalase 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 renalase; genetic deletion of renalase 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 seq analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature, as well as suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma renalase levels trended lower at day 14 post-treatment.
Conclusions Kidney-targeted delivery of renalase agonist RP81MNP 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.
Targeted delivery of celastrol to glomerular endothelium and podocytes for chronic kidney disease treatment
