Caspase-1–deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis

Abstract

These results indicate that caspase-1 contributes to cisplatin-induced ARF and ATN (day 3). Furthermore, caspase-1 affects caspase-3 activation and apoptosis in cisplatin-induced ARF (day 2).

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity

“…Thus regulation of the expression of executioner caspases is crucial prior to the execution of cell death. Several studies including ours have previously demonstrated activation of executioner caspases (caspase-3/7 and -6) in both in vitro 12,13 and in vivo 14,15 models of cisplatin-induced AKI. Similarly, induction of p53 transcription factor was demonstrated in RTECs in both in vitro [16][17][18] and in vivo 19 studies of cisplatin AKI.…”

The Inflammasomes in Kidney Disease

“…86 The role of the inflammasome in acute renal failure is further strengthened by the finding that caspase-1-deficient mice are more resistant to various types of acute tubular injury, includingcisplatinandischemia-inducedacute renal failure. 82,84 Recently, Iyer and colleagues 63 confirmed a role for the NLRP3 inflammasome and ASC in acute ischemia/ reperfusion kidney injury in mice. The activation of the NLRP3 inflammasome by necrotic cells is secondary to the extracellular matrix components biglycan and hyaluronan and mitochondrial ATP acting through P2X 7 receptors.…”

“…Numerous studies in humans and animal models of acute renal disease show elevated levels of IL-1␤ and/or IL-18. These models include ischemia/reperfusion injury, toxin-induced (cisplatin) tubular injury in rodents, [82][83][84][85] and in urine bioprofiles of critically ill patients with ATN. 86 The role of the inflammasome in acute renal failure is further strengthened by the finding that caspase-1-deficient mice are more resistant to various types of acute tubular injury, includingcisplatinandischemia-inducedacute renal failure.…”

A Role for Tubular Necroptosis in Cisplatin-Induced AKI

“…It is apparent that the increase of RIP1 and RIP3 protein levels during cisplatin-induced AKI contributes to the necroptosis Blockade of Necroptotic Pathway Impairs the Induction of Some Proinflammatory Cytokines in Cisplatin-Induced AKI Model Inflammation in lesions has been shown to play an important role in the acceleration of cisplatin nephrotoxicity. 3,21 Cisplatin has been reported to induce cytokine production in renal tubular cells directly, 22 and necrotic death may also exacerbate inflammation. Therefore, we investigated whether blocking necroptosis by RIP3 deficiency affects cisplatin-induced inflammatory cytokine expression in proximal tubules in vivo.…”

“…1 Cell death and inflammation are found predominantly in the proximal tubule segment of the nephron, which coincides with the location of maximal cisplatin accumulation. 2,3 Morphologic analysis of cisplatin nephrotoxicity shows that most cellular damage in kidney tubules is caused by necrosis. 4,5 However, many previous studies have focused on apoptosis induced by cisplatin in renal tubular cells, perhaps because necrosis has long been considered to be an incidental and uncontrolled form of cell death.…”