Loss of sphingosine kinase 2 protects against cisplatin induced-kidney injury

Am J Physiol Renal Physiol. 2022 Jul 14. doi: 10.1152/ajprenal.00229.2021. Online ahead of print.ABSTRACTCisplatin is an established chemotherapeutic drug for treatment of solid-organ cancers, and is the primary drug utilized 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 the knockdown of SphK2 by siRNA blocked the cisplatin-induced increase of cellular injury markers, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-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 blotting and Immunostaining analysis. Furthermore, SphK2 inhibition suppressed cisplatin-induced increases of proinflammatory markers, NLR Family Pyrin Domain Containing 3 (NLRP3), Interleukin-1β and Interleukin-6. Genetic deletion of the SphK2 gene in mice further confirmed that the 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, in...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Source Type: research