Cold Storage Exacerbates Renal and Mitochondrial Dysfunction Following Transplantation

Shrum, Stephen; La, MacMillan-Crow; Parajuli, Nirmala

doi:10.4172/2472-1220.1000114

Cited by 12 publications

(21 citation statements)

References 23 publications

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“…Figure 6A shows a bottom-up proteomic analysis of latently infected kidney allografts at 3 hours, 24 hours, and 48 hours. Oxidative phosphorylation and mitochondrial dysfunction, typically activated pathways associated with transplant IRI, 34–36 such as cellular stress responses, including the DNA damage response, mitochondrial stress, and oxidative responses, were all activated after transplant compared with controls in both mice treated with IS or without IS. Figure 6B shows a protein analysis on plasma obtained from kidney recipients of latently infected allografts 48 hours posttransplant.…”

Section: Resultsmentioning

confidence: 96%

A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

Zhang

Qiu

Yan

et al. 2019

American Journal of Transplantation

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Reactivation of latent cytomegalovirus remains an important complication after transplant. Although immunosuppression (IS) has been implicated as a primary cause, we have previously shown that the implantation response of a kidney allograft can lead to early transcriptional activation of latent murine cytomegalovirus (MCMV) genes in an immune-competent host and to MCMV reactivation and dissemination to other organs in a genetically immune-deficient recipient. We now describe a model that allows us to separately analyze the impact of the implantation effect vs that of a clinically relevant IS regimen. Treatment with IS of latently infected mice alone does not induce viral reactivation, but transplant of latently infected allogeneic kidneys combined with IS facilitates MCMV reactivation in the graft and dissemination to other organs. The IS regimen effectively dampens allo-immune inflammatory pathways and depletes recipient anti-MCMV but does not affect ischemia-reperfusion injury pathways. MCMV reactivation similar to that seen in

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Section: Resultsmentioning

confidence: 96%

A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

Zhang

Qiu

Yan

et al. 2019

American Journal of Transplantation

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“…Indeed, aberrant complement activation is detected during acute and chronic allograft rejection in humans, but the direct connection between cold ischemia (during CS) and complement activation in renal graft is not clear. Here, we demonstrate, for the first time, that CS induces abnormal complement activity in rat renal transplants compared with ATx (no CS exposure), which correlates with graft dysfunction (26,27). This is the first study in an animal model, if any, to perform head-tohead comparisons in transplants with or without CS (but similar warm ischemia time during the transplant process), and these results highlight why prolonged CS produces unfavorable outcomes in the grafts after transplantation.…”

Section: Discussionmentioning

confidence: 57%

“…Our recent work with rat transplant models indicated that CS exacerbates renal damage and dysfunction in transplanted kidneys (compared with no CS) (25)(26)(27). We further demonstrated that proteasome function is decreased, protein homeostasis is altered, and albumin is modified within kidneys after CS plus transplantation (25,28).…”

Section: Introductionmentioning

confidence: 68%

Aberrant activation of the complement system in renal grafts is mediated by cold storage

Jiang

Stacks

et al. 2021

American Journal of Physiology-Renal Physiology

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Aberrant complement activation leads to tissue damage during kidney transplantation, and it is recognized as an important target for therapeutic intervention (6, 19, 35, 64). However, it is not clear whether cold storage (CS) triggers the complement pathway in transplanted kidneys. The goal of this study was to determine the impact of CS on complement activation in renal transplants. Male Lewis and Fischer rats were used, and donor rat kidneys were exposed to 4 h or 18 h of CS followed by transplantation (CS+Transplant). To study CS-induced effects, a group with no CS was included in which the kidney was removed and transplanted back to the same rat (autotransplantation, ATx). Complement proteins (C3 and C5b-9) were evaluated with western blotting (reducing and non-reducing conditions) and immunostaining. Western blot of renal extracts or serum indicated that the levels of C3 and C5b-9 increased after CS+Transplant compared to ATx. Quite strikingly, intracellular C3 was profoundly elevated within renal tubules after CS+Transplant but was absent in Sham or ATx groups, which showed only extratubular C3. Similarly, C5b-9 immunofluorescence staining of renal sections showed an increase in C5b-9 deposits in kidneys after CS+Transplant. Real-time PCR (SYBR Green) showed increased expression of CD11b and CD11c, components of complement receptors 3 and 4, respectively, as well as inflammatory markers such as TNF-α. In addition, recombinant TNF-α significantly increased C3 levels in renal cells. Collectively, these results demonstrate that CS activates the complement system in renal transplants.

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“…Given that prolonged CS followed by warm IRI produces ROS [37,39], and that ROS modulate the constitutive proteasome function [144][145][146], we can postulate that CS/Tx-mediated ROS could trigger denaturation of intracellular proteins and modulation of the constitutive proteasome function. Indeed, a recent report demonstrated that the chymotrypsin-like activity of the proteasome was compromised after renal CS/Tx [147], and that this correlated with severe renal dysfunction [80,90]. A study performed by using pharmacological inhibition of chymotrypsin-like activity of the proteasome during warm IRI showed aggravated renal damage [148].…”

Section: The Proteasomementioning

confidence: 99%

“…Studies further suggest that more severe mitochondrial respiratory dysfunction occurs after CS/Tx (cold ischemia + warm IRI) than transplantation without CS (only warm IRI) and further revealed that CS/Tx decreases the function of mitochondrial complexes I, II, III, and V [80]. Mitochondrial respiratory dysfunction during renal CS/Tx leads to reduced levels of ATP, accumulation of ROS, and increased renal damage, suggesting that the "damage" signals from CS likely begin with alterations in mitochondrial function [37,80,[84][85][86][87][88][89][90]. Normally, mitochondrial ROS are primarily detoxified by manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme.…”

Section: Mitochondrial Respiratory Complex and Rosmentioning

confidence: 99%

Targeting Mitochondria during Cold Storage to Maintain Proteasome Function and Improve Renal Outcome after Transplantation

Blaszak

2020

IJMS

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Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD). Compared to maintenance dialysis, kidney transplantation results in improved patient survival and quality of life. Kidneys from living donors perform best; however, many patients with ESKD depend on kidneys from deceased donors. After procurement, donor kidneys are placed in a cold-storage solution until a suitable recipient is located. Sadly, prolonged cold storage times are associated with inferior transplant outcomes; therefore, in most situations when considering donor kidneys, long cold-storage times are avoided. The identification of novel mechanisms of cold-storage-related renal damage will lead to the development of new therapeutic strategies for preserving donor kidneys; to date, these mechanisms remain poorly understood. In this review, we discuss the importance of mitochondrial and proteasome function, protein homeostasis, and renal recovery during stress from cold storage plus transplantation. Additionally, we discuss novel targets for therapeutic intervention to improve renal outcomes.

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Cold Storage Exacerbates Renal and Mitochondrial Dysfunction Following Transplantation

Cited by 12 publications

References 23 publications

A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

Aberrant activation of the complement system in renal grafts is mediated by cold storage

Targeting Mitochondria during Cold Storage to Maintain Proteasome Function and Improve Renal Outcome after Transplantation

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