Epoxyeicosatrienoic Acids Prevent Cisplatin-Induced Renal Apoptosis through a p38 Mitogen-Activated Protein Kinase–Regulated Mitochondrial Pathway

Abstract

Soluble epoxide hydrolase (sEH) catalyzes the conversion of epoxyeicosatrienoic acids into less active eicosanoids, and inhibitors of sEH have anti-inflammatory and antiapoptotic properties. Based on previous observations that sEH inhibition attenuates cisplatin-induced nephrotoxicity by modulating nuclear factor-kB signaling, we hypothesized that this strategy would also attenuate cisplatin-induced renal apoptosis. Inhibition of sEH with AR9273 [1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-ylurea)] reduced cisplatin-induced apoptosis through mechanisms involving mitochondrial apoptotic pathways and by reducing reactive oxygen species. Renal mitochondrial Bax induction following cisplatin treatment was significantly decreased by treatment of mice with AR9273 and these antiapoptotic effects involved p38 mitogen-activated protein kinase signaling. Similar mechanisms contributed to reduced apoptosis in Ephx2 2/2 mice treated with cisplatin. Moreover, in pig kidney proximal tubule cells, cisplatin-induced mitochondrial trafficking of Bax and cytochrome c, caspase-3 activation, and oxidative stress are significantly attenuated in the presence of epoxyeicosatrienoic acids (EETs). Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage.

Mitochondrial dysregulation and protection in cisplatin nephrotoxicity

“…Furthermore, knockout of Bax in mice leads to a significantly preservation of renal function under cisplatin treatment [9]. AR9273, an inhibitor of soluble epoxide hydrolase that inhibit the conversion of epoxyeicosatrienoic acids into less active eicosanoids, can also block mitochondrial Bax induction during cisplatin nephrotoxicity and interestingly, these anti-apoptotic effects may involve p38 mitogen-activated protein kinase (MAPK) signaling [56]. A recent study has further demonstrated that cisplatin-induced mitochondria dysfunction can be attenuated through increasing cGMP-dependent protein kinase I (PKG-I) activity.…”

Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

“…NSAIDinduced intestinal ulcers are characterized by apoptosis of intestinal epithelial cells (Harada et al, 2015). EETs, sEH inhibition, and sEH gene deletion decrease apoptosis of cells (Luo et al, 2010;Liu et al, 2013). Therefore, an antiapoptotic role of TPPU in intestinal epithelial cells may be expected.…”

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

“…Mitogenic actions of EETs are dependent on activation of Src kinase and initiation of a tyrosine kinase phosphorylation cascade (27). EETs also prevent cisplatin-induced apoptosis in LLC-PK1 cells by preventing mitochondrial trafficking of Bax and cytochrome C and caspase 3 activation (82). Taken together, EETs have actions at the proximal tubule that promote sodium excretion, prevent cell death, and enhance cellular regeneration.…”

“…EET analogs attenuate cisplatin-induced nephrotoxicity through a reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase 12 expression, and reduced caspase 3 activity (72). Likewise, EETs in LLC-PK1 epithelial cells attenuates mitochondrial trafficking of Bax and cytochrome c resulting in decreased caspase 3 activity and oxidative stress (82). Interestingly, the renal endothelial and epithelial antiapoptotic actions of EETs appear to work in concert with anti-inflammatory actions (72, 73, 82).…”