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Donor kidney injury molecule‐1 promotes graft recovery by regulating systemic necroinflammation
Author(s) -
Lee Ji Yun,
Ismail Ola Z.,
Zhang Xizhong,
Haig Aaron,
Lian Dameng,
Gunaratnam Lakshman
Publication year - 2018
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14745
Subject(s) - medicine , proinflammatory cytokine , kidney , hmgb1 , kidney transplantation , transplantation , inflammation , immunology , acute kidney injury , cancer research
Ischemia‐reperfusion injury during kidney transplantation predisposes to delayed graft function, rejection, and premature graft failure. Exacerbation of tissue damage and alloimmune responses may be explained by necroinflammation: an autoamplification loop of cell death and inflammation, which is mediated by the release of damage‐associated molecular patterns (eg, high‐mobility group box‐1; HMGB 1) from necrotic cells that activate both innate and adaptive immune pathways. Kidney injury molecule‐1 ( KIM ‐1) is a phosphatidylserine receptor that is upregulated on injured proximal tubular epithelial cells and enables them to clear apoptotic and necrotic cells. Here we show a pivotal role for clearance of dying cells in regulating necroinflammation in a syngeneic murine kidney transplant model. We found persistent KIM ‐1 expression in KIM ‐1 +/+ kidney grafts posttransplantation. Compared to recipients of KIM ‐1 +/+ kidneys, recipients of KIM ‐1 −/− kidneys exhibited significantly more renal dysfunction, apoptosis and necrosis, tubular obstruction, and graft failure. KIM ‐1 −/− grafts also had more inflammatory cytokines, infiltrating neutrophils, and macrophages compared to KIM ‐1 +/+ grafts. Most significantly, passive release of HMGB 1 from apoptotic and necrotic cells led to dramatically higher serum HMGB 1 levels and increased proinflammatory macrophages in recipients of KIM ‐1 −/− grafts. Our data identify an endogenous protective mechanism against necroinflammation in kidney grafts that may be of therapeutic relevance in transplantation.