Pitavastatin Improves Doxorubicin-Induced Nephrotic Syndrome by Inhibiting the IL-13/p-STAT6 Pathway

Abstract

Background: Doxorubicin (DOX) is a commonly used antineoplastic medication in clinical settings. However, its clinical utility is hampered by pronounced adverse effects such as nephrotoxicity. The interleukin (IL)-13/p-signal transducer and activator of transcription 6 (STAT6) pathway plays a critical role in various renal diseases. Furthermore, Pitavastatin, a statin drug, has been recognized for its protective effects against multiple diseases. Therefore, this study aimed to explore whether Pitavastatin could improve doxorubicin-induced experimental nephrotoxicity by inhibiting the IL-13/p-STAT6 pathway. Methods: In this study, a doxorubicin-induced mouse model of renal injury was employed, and mice were randomly divided into five groups: the normal control, Pitavastatin, doxorubicin, doxorubicin + dimethyl sulfoxide (DMSO), and doxorubicin + Pitavastatin groups. Their renal function was assessed by observing mouse body weight and serum biochemical markers (urea nitrogen, creatinine, cystatin C). Western blot analysis was used to examine the levels of IL-13 and STAT6, their phosphorylation in renal tissues, and the expression of inflammatory factors. The effects of Pitavastatin on doxorubicin-induced oxidative stress and apoptosis were analyzed through 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Results: Compared to the doxorubicin group, the doxorubicin + Pitavastatin group showed a significant reduction in mouse body weight and improvement in serum biochemical markers (p < 0.05), indicating that Pitavastatin effectively ameliorated doxorubicin-induced nephrotoxicity. Furthermore, Pitavastatin suppressed the IL-13/p-STAT6 pathways activity and reduced the expression of inflammatory factors at the molecular level. Additionally, Pitavastatin alleviated doxorubicin-induced oxidative stress and apoptosis. Conclusion: This study demonstrates that Pitavastatin can alleviate doxorubicin-induced nephrotoxicity by inhibiting the IL-13/p-STAT6 pathway. This effect may be correlated to its anti-inflammatory, antioxidant, and anti-apoptotic capabilities. Therefore, Pitavastatin can be a promising therapeutic drug for treating doxorubicin-induced nephrotoxicity. Furthermore, these findings offer a novel theoretical foundation for the therapeutic use of Pitavastatin and suggest future avenues for additional clinical investigations.