Normal Proteasome Function Is Needed to Prevent Kidney Graft Injury during Cold Storage Followed by Transplantation
-
Published:2024-02-10
Issue:4
Volume:25
Page:2147
-
ISSN:1422-0067
-
Container-title:International Journal of Molecular Sciences
-
language:en
-
Short-container-title:IJMS
Author:
Bhattarai Dinesh1ORCID, Lee Seong-Ok1, MacMillan-Crow Lee Ann1ORCID, Parajuli Nirmala12ORCID
Affiliation:
1. Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA 2. Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Abstract
Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD). However, there is a shortage of transplantable kidneys, and donor organs can be damaged by necessary cold storage (CS). Although CS improves the viability of kidneys from deceased donors, prolonged CS negatively affects transplantation outcomes. Previously, we reported that renal proteasome function decreased after rat kidneys underwent CS followed by transplantation (CS + Tx). Here, we investigated the mechanism underlying proteasome dysfunction and the role of the proteasome in kidney graft outcome using a rat model of CS + Tx. We found that the key proteasome subunits β5, α3, and Rpt6 are modified, and proteasome assembly is impaired. Specifically, we detected the modification and aggregation of Rpt6 after CS + Tx, and Rpt6 modification was reversed when renal extracts were treated with protein phosphatases. CS + Tx kidneys also displayed increased levels of nitrotyrosine, an indicator of peroxynitrite (a reactive oxygen species, ROS), compared to sham. Because the Rpt6 subunit appeared to aggregate, we investigated the effect of CS + Tx-mediated ROS (peroxynitrite) generation on renal proteasome assembly and function. We treated NRK cells with exogenous peroxynitrite and evaluated PAC1 (proteasome assembly chaperone), Rpt6, and β5. Peroxynitrite induced a dose-dependent decrease in PAC1 and β5, but Rpt6 was not affected (protein level or modification). Finally, serum creatinine increased when we inhibited the proteasome in transplanted donor rat kidneys (without CS), recapitulating the effects of CS + Tx. These findings underscore the effects of CS + Tx on renal proteasome subunit dysregulation and also highlight the significance of proteasome activity in maintaining graft function following CS + Tx.
Funder
NIH NIDDK American Heart Association UAMS Barton Pilot award
Reference59 articles.
1. Global epidemiology of end-stage kidney disease and disparities in kidney replacement therapy;Thurlow;Am. J. Nephrol.,2021 2. Steichen, C., Giraud, S., Bon, D., Barrou, B., Badet, L., Salamé, E., Kerforne, T., Allain, G., Roumy, J., and Jayle, C. (2018). Barriers and advances in kidney preservation. BioMed Res. Int., 2018. 3. van Eck van der Sluijs, A., Vonk, S., van Jaarsveld, B.C., Bonenkamp, A.A., and Abrahams, A.C. (2021). Good practices for dialysis education, treatment, and eHealth: A scoping review. PLoS ONE, 16. 4. Clinical characteristics of deceased hemodialysis patients affected by COVID-19;Min;Int. Urol. Nephrol.,2021 5. Design, implementation, and evaluation of a knowledge translation intervention to increase organ donation after cardiocirculatory death in Canada: A study protocol;Squires;Implement. Sci.,2014
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
1. Out of the Cold;Kidney360;2024-05
|
|