Apoptosis and acute kidney injury

Abstract

Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the 'perfect storm' for outer mitochondrial membrane injury to release its cellular 'executioners'. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.

Figure 1. Simplified representation of major intrinsic and extrinsic signal events known to promote apoptosis in renal cells exposed to stress

Life and death signals are integrated by the mitochondrion and determine whether or not MPT occurs, resulting in the release of both caspase-dependent and -independent factors that promote apoptosis from the intramembranous space. Caspase activation and DNA fragmentation produce many of the characteristic morphological changes associated with apoptotic cell death after exposure to stress, nephrotoxins, ROS, DNA injury, activation of stress kinases, or removal of extrinsic factors that normally suppress apoptosis. AIF, apoptosis-inducing factor; Akt, protein kinase B; Bax, Bad, Bak, BID, and truncated or t-Bid are proapoptotic BCL2 proteins; Bcl2, anti-apoptotic BCL2 protein; Cyto c, cytochrome c; ERK1/2, extracellular regulated kinase 1/2; FasL or CD95, FAS ligand; GSK3β, glycogen synthase kinase 3-β; Hsp, heat stress protein; JNK, Jun-N-terminal kinase; MPT, outer mitochondrial membrane pore transition; p38, mitogen-activated protein kinase; p53, a tumor-suppressor protein; PI3k, phosphatidylinositol 3-kinase; ROS, reactive oxygen species generated by mitochondria or other sources; TNF-α, tumor necrosis factor-α; TWEAK, TNF-related weak inducer of apoptosis. ERK1/2 and JNK are stress-regulated kinases; Hsp70 is heat stress protein 70 kDa, an antiapoptotic protein; Hsp27 is heat stress protein 27 kDa; FasL or CD95 is a TNF family member.

Figure 2. Mitochondrial morphology in primary proximal tubule cells at baseline (Control) and during adenosine-5′-triphosphate (ATP) depletion using MitoTracker red (Invitrogen, Carlsbad, CA)

Filamentous mitochondria undergo fragmentation, resulting in small, punctuate organelles during ATP depletion; an in vitro model of ischemic injury.