Abstract
Reperfusion injury following cold and warm ischemia (IRI) is unavoidable during kidney transplantation and contributes to delayed graft function (DGF) and premature graft loss. Death of tubular epithelial cells (TECs) by necrosis during IRI releases pro-inflammatory mediators (e.g. HMGB1), propagating further inflammation (necroinflammation) and tissue damage. Kidney Injury Molecule-1 (KIM-1) is a phagocytic receptor upregulated on proximal TECs during acute kidney injury. We have previously shown that renal KIM-1 protects the graft against transplant associated IRI by enabling TECs to clear apoptotic and necrotic cells, and that recognition of necrotic cells by KIM-1 is augmented in the presence of the opsonin, apoptosis inhibitor of macrophages (AIM). Here, we tested whether recombinant AIM (rAIM) could be used to mitigate transplant associated IRI. We administered rAIM or vehicle control to nephrectomised B6 mice transplanted with a single B6 donor kidney. Compared to grafts in vehicle-treated recipients, grafts from rAIM-treated mice exhibited significantly less renal dysfunction, tubular cell death, tissue damage, tubular obstruction, as well as local and systemic inflammation. Both mouse and human rAIM enhanced the clearance of necrotic cells by murine and human TECs, respectively in vitro. These data support testing of rAIM as a potential therapeutic agent to reduce DGF following kidney transplantation.
Highlights
Reperfusion injury following cold and warm ischemia (IRI) is an unavoidable consequence of renal transplantation
Transcript analysis of transplanted kidneys revealed that grafts from recombinant AIM (rAIM) treated mice had significantly less expression of pro-inflammatory genes: IL-6 (1.478 ± 0.3042 vs. 25.61 ± 8.566, p = 0.0306), MIP-2α (19.79 ± 4.45 vs. 158.8 ± 57.65, p = 0.0352), and IL-1β compared to grafts from PBS treated controls (39.71 ± 7.822 vs. 142.1 ±34.11, p = 0.0264; Fig 2E)
Kidney grafts from mice treated with rAIM appeared to be more repaired with minimal intraluminal debris when compared to grafts from mice treated with PBS
Summary
Reperfusion injury following cold and warm ischemia (IRI) is an unavoidable consequence of renal transplantation. We observed greater renal and systemic inflammation as well as increased susceptibility to renal dysfunction and tissue damage, compared to transplanted kidneys from wild-type donors [18] Taken together, these studies suggest that KIM-1 plays a protective role in mitigating tissue damage by inhibiting necroinflammation [18]. The anti-inflammatory and therapeutic effects of rAIM in renal transplantation has not been studied To this end, we tested whether recombinant AIM can be used as a potential therapeutic agent to improve renal recovery after transplantation of kidneys exposed to severe warm and cold ischemia. We hypothesized that administration of exogenous recombinant AIM would augment KIM1-mediated clearance of necrotic cells, mitigating necroinflammation, tissue damage, and renal dysfunction after transplantation of kidneys exposed to severe IRI
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
