Inhibition of PTEN activity aggravates cisplatin-induced acute kidney injury

Abstract

Cisplatin (cis-Diamminedichloroplatinum II) has been widely and effectively used in chemotherapy against tumors. Nephrotoxicity due to cisplatin is one of the most common clinical causes of acute kidney injury (AKI), which has a poor prognosis and high mortality. The signaling mechanisms underlying cisplatin-induced AKI are not completely understood. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor that negatively regulates the cell-survival pathway and is considered a double-edged sword in organ damage. In this study, we examined the effect that inhibiting PTEN activity in experimental models of cisplatin-induced AKI had on the degrees of AKI. Compared with vehicle mice, mice treated with bpV(pic) (specific inhibitor of PTEN) had exacerbated renal damage due to cisplatin-induced AKI. Furthermore, inhibition of PTEN activity increased cell apoptosis in the kidneys of mice induced by cisplatin. More inflammatory cytokines were activated after cisplatin treatment in mice of the bpV(pic)-treated group compared with vehicle mice, and these inflammatory cytokines may be partially derived from bone marrow cells. In addition, inhibiting PTEN activity decreased the phosphorylation of p53 in the pathogenesis of cisplatin-induced AKI. In summary, our study has demonstrated that inhibiting PTEN activity aggravates cisplatin-induced AKI via apoptosis, inflammatory reaction, and p53 signaling pathway. These results indicated that PTEN may serve as a novel therapeutic target for cisplatin-induced AKI.

Genetic Determinants of Obesity Heterogeneity in Type II Diabetes

“…back into PIP2 and reversing the effects of PI3K/AKT pathway [31]- [33], its transmembrane function might be more imperative than its intracellular function [34]- [36].…”

Gene Expression Pattern of PI3K/AKT Pathway Based on Insulin Resistance and Vitamin D Toward the Understanding of T2DM Pathogenesis

“…It means that the main role of PTEN in regulation of insulin function is performed by dephosphorylating the active form (insulin-stimulated) of insulin receptor and by modulating postreceptor signalling through antagonizing PI3K/AKT pathway [19]- [21]. These findings indicates that PTEN's transmembrane function is probably more imperative than its intracellular function in insulin signal attenuation.…”

Gene Expression Pattern of PI3K/AKT Pathway Based on Insulin Resistance and Vitamin D Toward the Understanding of T2DM Pathogenesis

“…Although the necessity of the PI3K/AKT pathway in insulin signal transduction is documented [18], it has not attained sufficient in vivo and in vitro evidence to identify the underlying mechanisms of the pathway and contradictory findings have been reported through knockout and RNAi studies [19]- [21].…”

“…This may lead one to the hypothesis that localization of PTEN plays an important role in the regulation of its activity [60]- [63]. It means that the main role of PTEN in the regulation of insulin function is performed by dephosphorylating the active form (insulin-stimulated) of the insulin receptor and also by modulating post-receptor signalling through antagonizing PI3K/AKT pathway [19]- [21] and indicating that PTEN's transmembrane function is probably more imperative than its intracellular function in insulin signal attenuation.…”