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.

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.

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.

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.

重复给予顺铂会导致 CKD。在之前的研究中，我们报道了肾脏分泌的存活蛋白肾酶 (RNLS) 和激动剂肽可保护小鼠免受顺铂诱导的 AKI。

为了研究 RNLS 的肾脏靶向递送是否可以预防小鼠模型中顺铂诱导的 CKD，我们通过将肽封装在中尺度纳米颗粒 (MNP) 中，实现了将 RNLS 激动剂肽 (RP81) 特异性递送至肾近端小管。我们使用 RNLS 基因缺失、单细胞 RNA 测序分析和蛋白质印迹来确定疗效并探索潜在机制。我们还测量了接受首剂顺铂化疗的晚期头颈部鳞状细胞癌患者的血浆 RNLS。

在顺铂诱导的 CKD 小鼠中，我们观察到肾脏 RNLS 减少了大约 60%；RNLS 的基因缺失与明显更严重的顺铂诱导的 CKD 相关。在这种顺铂诱导的 CKD 严重模型中，全身给药 MNP 封装的 RP81 (RP81-MNP) 可显着降低 CKD，如血浆肌酐和组织学所评估的那样。它还能减少血浆中的炎性细胞因子并抑制肾脏中受调节的坏死。单细胞 RNA 测序分析表明，RP81-MNP 保留了肾单位和脉管系统的上皮成分，并抑制了炎症性巨噬细胞和肌成纤维细胞。在接受首剂顺铂化疗的患者中，血浆 RNLS 水平在治疗后第 14 天呈下降趋势。

RNLS 激动剂 RP81-MNP 的肾脏靶向递送通过减少细胞死亡和提高肾近端小管的活力来防止顺铂诱导的 CKD。这些发现表明，这种方法可能会减轻接受顺铂癌症化疗的患者 CKD 的发展。