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

J Am Soc Nephrol. 2022 Feb;33(2):342-356. doi: 10.1681/ASN.2021040439. Epub 2021 Dec 17.


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.

Keywords: cell death; chronic renal disease; cisplatin; cisplatin nephrotoxicity; cytokines; macrophages; mitochondria; oxidative stress; proximal tubule; renal protection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Cell Line
  • Cisplatin / administration & dosage
  • Cisplatin / adverse effects*
  • Creatinine / blood
  • Disease Models, Animal
  • Gene Expression / drug effects
  • Glomerular Filtration Rate
  • Hepatitis A Virus Cellular Receptor 1 / blood
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoamine Oxidase / deficiency
  • Monoamine Oxidase / genetics
  • Monoamine Oxidase / metabolism*
  • Nanocapsules / administration & dosage
  • Peptides / administration & dosage
  • Peptides / genetics
  • Renal Insufficiency, Chronic / chemically induced*
  • Renal Insufficiency, Chronic / pathology
  • Renal Insufficiency, Chronic / prevention & control*


  • Antineoplastic Agents
  • HAVCR1 protein, human
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Nanocapsules
  • Peptides
  • Creatinine
  • Monoamine Oxidase
  • renalase
  • Cisplatin