Distinct Transcriptional Changes in Donor Kidneys upon Brain Death Induction in Rats: Insights in the Processes of Brain Death

Abstract

Brain death affects hormone regulation, inflammatory reactivity and hemodynamic stability. In transplant models, donor organs retrieved from brain dead (BD) rats suffer from increased rates of primary nonfunction and lower graft survival. To unravel the mechanisms behind brain death we have performed DNA microarray studies with kidney-derived RNA from normo-and hypotensive BD rats, corresponding with optimal and marginal BD donors, respectively. In kidneys from normotensive donors 63 genes were identified as either up-(55) or down-regulated (8), while 90 genes were differentially expressed (67 up-regulated) in hypotensive BD donor kidneys. Most genes were categorized in different functional groups: metabolism/transport (including the down-regulated water channel Aqp-2), inflammation/coagulation (containing the largest number (16) of up-regulated genes including selectins, Il-6, a -and b -fibrinogen), cell division/fibrosis (including KIM-1 involved in tubular regeneration) and defense/repair (with the cytoprotective genes HO-1, Hsp70, MnSOD2). Also, genes encoding transcription factors (including immediate early genes as Atf-3, Egr-1) and proteins involved in signal transduction (Pik3r1) were identified. Summarizing, the use of DNA microarrays has clarified parts of the process of brain death: Brain-death-induced effects ultimately lead, via activation of transcription factors and signal transduction cascades, to differential expression of different "effector" genes. Not only deleterious processes such as inflammation and fibrosis occur in brain dead donor kidneys but genes involved in protection and early repair processes are activated as well. These findings can be used to introduce specific cytoprotective interventions in the brain dead donor to better maintain or even increase organ viability.

Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury

“…The presence of Fg␣, Fg␤, and Fg␥ chain transcripts in the kidney at baseline 11 as well as its up-regulation after nephrotoxicity 31 or brain death-induced vascular endothelial activation in kidneys 12,32 has been observed previously. Here, we characterized the cellular expression patterns of Fg and its individual chains in the renal tubule after injury.…”

Early Events in Kidney Donation: Progression of Endothelial Activation, Oxidative Stress and Tubular Injury After Brain Death

“…Under hemodynamic and rheological unstable conditions, endothelial cells have demonstrated their ability to sense variations in mechanical forces, such as shear stress, that appear as a consequence of blood flow and viscosity alterations (4,5). Numerous studies suggest that immune activation with increased endothelial cell activation and immediate early gene expression occurs after BD induction (6)(7)(8)(9). Moreover, the expression of endothelial adhesion molecules ICAM-1 and VCAM-1 and the influx of leukocytes in the kidney are shown to occur faster and be more profound when hemodynamic instability in the brain dead donor is not corrected (10).…”

Brain death-associated pathological events and therapeutic options

“…Additionally, the downregulation of aquaporin-2 channels caused by BD aggravates the decline of hemodynamic stability. 32 To maintain adequate blood pressure, hormonal replacement therapy with vasopressin is advised. 33 Lowdose vasopressin therapy, when compared to fluid volume replacement, improves blood pressure, decreases inotrope requirements and preserves levels of myocardial high energy phosphates, and allows for the reduction of catecholamine supply.…”