Cisplatin is an established chemotherapeutic drug for treatment of solid-organ
cancers and is the primary drug used in the treatment of
head and neck cancer; however,
cisplatin-induced nephrotoxicity largely limits its clinical use. Inhibition of
sphingosine kinase 2 (SphK2) has been demonstrated to alleviate various
kidney diseases. Therefore, we hypothesized that inhibition of SphK2 could also protect against
cisplatin-induced nephrotoxicity. Results from the present study showed that the SphK2 inhibitor
ABC294640 or knockdown of SphK2 by
siRNA blocked the
cisplatin-induced increase of cellular injury markers (
neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and cleaved
caspase-3) by Western blot analysis in HK-2 cells, a human renal tubular cell line. In addition, SphK2 inhibition blocked
cisplatin-induced activation of NF-κB by Western blot analysis and immunostaining analysis. Furthermore, SphK2 inhibition suppressed
cisplatin-induced increases of proinflammatory markers (NLR family pyrin domain containing 3,
interleukin-1β, and
interleukin-6). Genetic deletion of the SphK2 gene in mice further confirmed that inhibition of SphK2 protected against
cisplatin-induced kidney damage in vivo. Compared with wild-type mice, SphK2 knockout mice exhibited less renal dysfunction and reduced promotion of kidney injury markers, inflammatory factors, tubular morphology damage, and fibrotic staining. At the same time, the SphK2 inhibitor
ABC294640 failed to interfere with the activity of
cisplatin or radiation in two cell culture models of
head and neck cancer. It is concluded that inhibition of Sphk2 protects against
cisplatin-induced kidney injury. SphK2 may be used as a potential therapeutic target for the prevention or treatment of
cisplatin-induced kidney injury.NEW & NOTEWORTHY The present study provides new findings that
sphingosine kinase 2 (SphK2) is highly expressed in renal tubules,
cisplatin treatment increases the expression of SphK2 in proximal tubular cells and kidneys, and inhibition of SphK2 alleviates
cisplatin-induced kidney injury by suppressing the activation of NF-κB, production of inflammatory factors, and apoptosis. SphK2 may serve as a potential therapeutic target for the prevention or treatment of
cisplatin-induced nephrotoxicity.