Most Important Cellular Changes Involved in Renal Ischemia Reperfusion Injury and the Consequent Impact on Selected Remote Organs

Abstract

Because of the high rate of baseline oxygen use by renal cells, kidney is highly influenced by obstruction of arterial blood inflow and subsequent shortage of the received oxygen, this condition is known as Ischemic injury. There are many clinical settings associated with unavoidable ischemic state such as kidney transplantation, partial nephrectomy or suprarenal procedures of the aorta. During ischemia many cellular changes occur including vascular congestion and adhesion of inflammatory cells to the endothelium with subsequent infiltration into the kidney tissue. Following ischemia, a phase known as Reperfusion begins and involves a return of blood and oxygen supply to micro vessels. Reperfusion was expected to restore the damage occurred during the ischemic phase, paradoxically, reperfusion leads to more congestion, red cells trapping and excessive generation of reactive oxygen species (ROS), which can oxidatively modify significantly every type of biomolecule, thereby inducing cell dysfunction and induce reperfusion injury. Ischemia reperfusion injury (IRI) is also related to a phenomenon called Remote Organ Injury (ROI) in which the damaging effect induced by I/R is not only restricted to the tissue that undergoing the initial ischemia but also it leads to injury to remote organs such as the liver, lung, gut. ROI usually occurs by the same mechanisms seen in the local injury induced by I/R including the generation of ROS, leukocytes, and inflammatory mediators (e.g; TNF-α). These substances are directly released from the primary injured tissue or indirectly from activated leukocytes or other inflammatory cells causing organ dysfunctions in distant organs.

Effect of Aliskiren on Renal Cortical Ischemia/Reperfusion Injury in Albino Rats: A Histological and Immunohistochemical Study

“…The renal cortex has the highest level of oxygenation followed by the outer medulla, and the lowest levels in the inner medulla and papillae. Consequently, the cortical cells are the most susceptible to ischemia, while cells in the outer medulla can alter to metabolism independent on oxygen, and the inner medullary and papillae cells depend mainly on anaerobic glycolysis [25] .…”

“…It is worth to mention that during ischemia, all the nephron segments can be affected, but the PCT cells are usually the most injured; because they have a high metabolic rate plus a limited capacity to carry out anaerobic glycolysis [25] . On the contrary, DCT have a greater capacity to change to glycolytic metabolism, hence adapt better to ischemia.…”

“…Following ischemia, the injured PCT cells generate a number of potent mediators including pro-inflammatory cytokines as tumor necrosis factor (TNF), and interleukins (IL) -6, -1β and -8. Also, the extravasated leucocytes release toxic ROS, elastases and proteases, leading to increased microvascular permeability, thrombosis and parenchymal cell death [18,25] .…”

“…During hypoxia, there is accumulation of intracellular calcium that results in caspase activation in ischemic tissues and is an indicator of cell death [12] . Besides, following the decrease in effective kidney perfusion, epithelial cells cannot preserve sufficient intracellular ATP for essential processes, so cell death by necrosis or apoptosis occurs [25] . Adding up, oxidative stress leads to activation of the proapoptotic Bax protein, which is mainly localized in renal tubular cells, and it plays an important role in the apoptotic cascade, where it promotes caspase-3 activation [21] .…”