Kidney-Targeted Renalase Agonist Prevents Cisplatin-Induced Chronic Kidney Disease by Inhibiting Regulated Necrosis and Inflammation.
Amino Acid Sequence
Animals
Antineoplastic Agents
/ administration & dosage
Cell Line
Cisplatin
/ administration & dosage
Creatinine
/ blood
Disease Models, Animal
Gene Expression
/ drug effects
Glomerular Filtration Rate
Hepatitis A Virus Cellular Receptor 1
/ blood
Humans
Kidney
/ drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Monoamine Oxidase
/ deficiency
Nanocapsules
/ administration & dosage
Peptides
/ administration & dosage
Renal Insufficiency, Chronic
/ chemically induced
cell death
chronic renal disease
cisplatin
cisplatin nephrotoxicity
cytokines
macrophages
mitochondria
oxidative stress
proximal tubule
renal protection
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
12
05
2021
accepted:
12
11
2021
pubmed:
19
12
2021
medline:
5
3
2022
entrez:
18
12
2021
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 34921111
pii: 00001751-202202000-00009
doi: 10.1681/ASN.2021040439
pmc: PMC8819981
doi:
Substances chimiques
Antineoplastic Agents
0
HAVCR1 protein, human
0
Havcr1 protein, mouse
0
Hepatitis A Virus Cellular Receptor 1
0
Nanocapsules
0
Peptides
0
Creatinine
AYI8EX34EU
Monoamine Oxidase
EC 1.4.3.4
renalase
EC 1.4.3.4.
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
342-356Subventions
Organisme : NIDDK NIH HHS
ID : RC1 DK086402
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079310
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC1 DK086465
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK081037
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK120783
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 by the American Society of Nephrology.
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