Section of Nephrology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
Veterans Affairs Medical Center, West Haven, Connecticut.
J Am Soc Nephrol. 2022 Feb;33(2):342-356. doi: 10.1681/ASN.2021040439. Epub 2021 Dec 17.
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.
顺铂重复给药会导致慢性肾脏病（CKD）。在之前的研究中，我们报道了肾脏分泌的生存蛋白肾酶（RNLS）和激动肽可保护小鼠免受顺铂诱导的急性肾损伤（AKI）。
为了研究肾脏靶向递送 RNLS 是否可以预防小鼠模型中顺铂引起的 CKD，我们通过将肽包裹在中尺度纳米颗粒（MNP）中，实现了 RNLS 激动肽（RP81）对肾近端小管的特异性递送。我们使用 RNLS 基因缺失、单细胞 RNA 测序分析和 Western blot 来确定疗效并探索潜在机制。我们还测量了接受首次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 减少了约 60%；RNLS 的基因缺失与更严重的顺铂诱导的 CKD 显著相关。在这种严重的顺铂诱导的 CKD 模型中，全身给予 MNP 包裹的 RP81（RP81-MNP）可显著减少 CKD，其评估指标为血浆肌酐和组织学。它还降低了血浆中的炎症细胞因子，并抑制了肾脏中的调节性细胞坏死。单细胞 RNA 测序分析显示，RP81-MNP 可保留肾单位的上皮成分和血管，并抑制炎症性巨噬细胞和肌成纤维细胞。在接受首次顺铂化疗的患者中，治疗后第 14 天血浆 RNLS 水平呈下降趋势。
肾脏靶向递送 RNLS 激动肽 RP81-MNP 通过减少细胞死亡和改善肾近端小管的活力来预防顺铂诱导的 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。
