A possible mechanism of renal cell death after ischemia/reperfusion

Abstract

Linkermann et al. provide the first evidence for a possible biochemical mechanism of necrotic kidney cell death associated with renal ischemia/reperfusion-induced acute kidney injury. The mechanisms of several pathways resulting in programmed necrosis were recently elucidated and rely on receptor-interacting protein kinases 1 and 3. Using an inhibitor of one of these kinases, Linkermann et al. were able to ameliorate functional and morphologic kidney damage after ischemia/reperfusion.

Figure 1

Binding of the TNFα ligand to its receptor, TNFR1, leads to recruitment of TNF receptor-associated death domain (TRADD). These proteins associate with other cytoplasmic proteins, including RIP1, TNF receptor-associated factors (TRAFs), and cellular inhibitor of apoptosis proteins (cIAPs) to form Complex 1. Complex 1 can also activate NF-κB and thereby transcription of FLICE-like inhibitory protein long (FLIP). Several steps later, the RIP1-associated complex can functionally interact with RIP3 and caspase-8, forming Complex 2. With high levels of FLIP, the complex does not result in RIP3 signaling and cell death is averted. Without FLIP, as with cycloheximide (CHX) addition, caspase-8 activation predominates and apoptosis results. When caspase-8 is inhibited, as with zVAD addition, RIP3 kinase is activated, resulting in programmed necrosis, or necroptosis. Necrostatin-1 blocks the kinase activity of RIP1, which is necessary for both apoptotic and necrotic pathways directed by Complex 2. Not shown here, in a similar death receptor mediated pathway, ligand binding to CD95/Fas induces a conformational change in the receptor, which promotes the assembly of a complex with Fas-associated death domain (FADD) and caspase-8. Similarly to the TNF pathway, FLIP can prevent caspase-8 apoptosis and cycloheximide addition can promote cell death.