Suggestions for attenuation of renal ischemia reperfusion injury based on mechanisms involved in epithelial cells damages

Renal I/R (ischemia reperfusion) occurs in kidney surgeries such as partial nephrectomy or transplantation because of renal vessels ligation during the procedures. Ischemia (tissue hypoxia) leads to renal damages especially proximal convoluted tubules (PCT) injuries (1-3). Serious damages also occur during and following reperfusion. Mechanisms that I/R damage proximal tubules cells are briefly explained below. Ischemia decreases ATP production and finally leads to tissue ATP depletion. ATP depletion leads to Rho GTPase inactivation that makes activation of ADF (Actin depolymerizing factor) or cofilin in the apical brush border of proximal tubules (4-6). Activated cofilin (ADF) rapidly depolymerizes apical actin cytoskeleton and redistribution. Deterioration of microvillar structure leads to formation of membrane blebs, which may be either internalized or shed into the tubular lumen. Brush border membrane components that are released into the lumen give to cast formation and tubular occlusion (7). ATP depletion also dissociates the actin-stabilizing proteins such as tropomyosin and ezrin (8), permitting the activated cofilin to bind and then depolymerize actin, which finally leads to microvillar breakdown. Activation of cofilin also can induce apoptosis in PCT cells by inducing release of cytochrome C from mitochondria to cytoplasm (9). PCT cell death occurs from at least two cell death mechanisms, necrosis and apoptosis. Activation of cofilin after ATP depletion also can induce apoptosis by activating intrinsic pathway (9) and also extrinsic pathway. Do not forget inhibition of apoptosis acts as double blade sword because, inhibition of apoptosis will promote survival of injured or mutation-bearing cells in other organ systems (10). Remember that apoptosis is the powerful normal mechanism for removal of genomic damaged cells. Challenges for the future clinical use of apoptosis inhibition in acute kidney injury (AKI) include determining the best timing of therapy, optimizing the specificity of inhibitor, minimizing the extra renal adverse effects, and tubule-specific targeting of the apoptosis modulatory maneuvers (10). In my opinion inhibition of apoptosis inducer such as cofilin in this issue is safer than inhibition of apoptosis pathways. Interruption of the apical cytoskeleton by ATP depletion also results in loss of tight junctions and adherents junctions between tubular cells and leads to tubular cells disconnection (11). Ischemia leads to disruption of at least two proteins, Na, 1Department of Anatomy, Faculty of Medicine, Lorestan University of Medical sciences, Khoram Abad, Iran