Mannan‐Binding Lectin Recognizes Structures on Ischaemic Reperfused Mouse Kidneys and is Implicated in Tissue Injury

Abstract

Organ damage as a consequence of ischaemia and reperfusion (I/R) is a major clinical problem in an acute renal failure and transplantation. Ligands on surfaces of endothelial cells that are exposed due to the ischaemia may be recognized by pattern recognition molecules such as mannan-binding lectin (MBL), inducing complement activation. We examined the contribution of the MBL complement pathway in a bilateral renal I/R model (45 min of ischaemia followed by 24 h of reperfusion), using transgenic mice deficient in MBL-A and MBL-C [MBL double knockout (MBL DKO)] and in wildtype (WT) mice. Kidney damages, which were evaluated by levels of blood urea nitrogen (BUN) and creatinine, showed that MBL DKO mice were significantly protected compared with WT mice. MBL DKO mice, reconstituted with recombinant human MBL, showed a dose-dependent severity of kidney injury increasing to a comparable level to WT mice. Acute tubular necrosis was evident in WT mice but not in MBL DKO mice after I/R, confirming renal damages in WT mice. MBL ligands in kidneys were observed to be present after I/R but not in sham-operated mice. C3a (desArg) levels in MBL DKO mice were decreased after I/R compared with that in WT mice, indicating less complement activation that was correlated with less C3 deposition in the kidneys of MBL DKO mice. Our data implicate a role of MBL in I/R-induced kidney injury.

Gene Silencing of Complement C5a Receptor Using siRNA for Preventing Ischemia/Reperfusion Injury

“…22 On the other hand, using a mouse I/R injury model, we have demonstrated that the renal expression or deposition of C9 occurs early after reperfusion and is localized to cellular debris and injured tubular epithelial cells, which is consistent with our previous study 7,9 and is supported by the view that the complement pathway is crucially involved in renal I/R injury. 16,[23][24][25] In our present study, we extend the link between renal I/R injury and complement by demonstrating that specific blockade of C5aR expression using siRNA can prevent renal I/R injury. While the role of complement as an important component of renal I/R injury has been supported by previous studies, 2,26 -29 attempts to block renal I/R injury have been variably successful.…”

Activation of the Lectin Pathway by Natural IgM in a Model of Ischemia/Reperfusion Injury

“…Their studies suggest that C2 and MBL, but not C1q, are necessary for I/R injury. In addition, Moller-Kristensen et al (38) reported that the MBL-deficient mice were protected in the renal I/R model. Thus, these reports raised a question regarding the initial events following I/R.…”

Myeloperoxidase Is Critically Involved in the Induction of Organ Damage after Renal Ischemia Reperfusion

“…It has been shown that bound complement components are critical in the induction and propagation of I/R-induced organ damage after initial cellular damage and apoptosis. 29,30 Predominantly the murine MBL variant C is one of the first inflammatory factors observed to bind during early reperfusion. 31 Therefore, immunohistochemical staining was performed on early 2-hour reperfusion samples, to study the deposition of activated MBL-C. No differences were detected in the amount of MBL-C present in the cortico-medullary region on peritubular capillaries and in the interstitium of reperfused ischemic kidneys from either Mpo Ϫ/Ϫ or WT mice (Figure 4), suggesting similar levels of complement activation as a result of comparable ischemiainduced cellular damage and apoptosis in Mpo Ϫ/Ϫ and WT animals.…”