Journal Article

Protection of the Transplant Kidney from Preservation Injury by Inhibition of Matrix Metalloproteinases

Banerjee, Tamalina, Sawicka, Jolanta, Lin, Han-Bin, Beck, Gavin R., Sawicki, Grzegorz, Luo, Yigang, Luke, Patrick P., Moser, Michael A. J., Wojnarowicz, Chris, Arcand, Steve

2016

Overview

Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion. Human kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD). Markers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers. Based on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Analysis / Animal models / Animals / Biology and Life Sciences / Biomarkers / Biomarkers - metabolism / Brain / Cytochrome / Cytochrome oxidase / Cytochrome-c oxidase / Delayed Graft Function - enzymology / Delayed Graft Function - pathology / Donations / Doxycycline / Doxycycline - pharmacology / Electron Transport Complex IV - metabolism / Female / Gelatinase / Gelatinase A / Gelatinase B / Health aspects / Heart / Humans / Inhibitors / Injury analysis / Injury prevention / Ischemia / Kidney - drug effects / Kidney - injuries / Kidney - pathology / Kidney - ultrastructure / Kidney Transplantation / Kidneys / L-Lactate dehydrogenase / L-Lactate Dehydrogenase - metabolism / Lactate dehydrogenase / Lactic acid / Lipocalin / Lipocalin-2 - metabolism / Male / Markers / Matrix Metalloproteinase 2 - metabolism / Matrix Metalloproteinase 9 - metabolism / Matrix Metalloproteinase Inhibitors - pharmacology / Matrix metalloproteinases / Matrix Metalloproteinases - metabolism / Medicine and Health Sciences / Middle Aged / Mitochondria - drug effects / Mitochondria - metabolism / Models, Animal / Organ Preservation / Perfusion / Pharmacology / Physiological aspects / Physiology / Preservation / Proteins / Rats / Research and Analysis Methods / Rodents / siRNA / Supplements / Surgery / Transplants & implants