Abstract
Cisplatin is one of the most potent chemotherapy drugs to treat cancers, but its clinical application remains limited due to severe nephrotoxicity. Several approaches have been developed to minimize such side effects, notably including chronotherapy, a well-known strategy based on the circadian clock. However, the component of the circadian clock machinery that particularly responses to the cisplatin stimulation remains unknown, including its functions in cisplatin-induced renal injury. In our present study, we demonstrated that Bmal1, as a key clock gene, was induced by the cisplatin stimulation in the mouse kidney and cultured human HK-2 renal cells. Gain- and loss-of-function studies indicated that Bmal1 facilitated cisplatin-induced renal injury both in vivo and in vitro, by aggravating the cell apoptotic process. More importantly, RNA-seq analysis revealed that Bmal1 triggered the expression of hallmark genes involved in renal hepatization, a critical event accompanied by the injury. At the molecular level, Bmal1 activated the transcription of hepatization-associated genes through direct recruitment to the E-box motifs of their promoters. Our findings suggest that Bmal1, a pivotal mediator induced renal injury in response to cisplatin treatment, and the therapeutic intervention targeting Bmal1 in the kidney may be a promising strategy to minimize the toxic side-effects of cisplatin in its clinical applications.
Highlights
Cisplatin, a platinum-based chemotherapeutic agent, has been widely used in the treatment of various solid tumors, including lung, breast, esophageal, ovarian, and pancreatic cancers[1,2,3,4,5]
We found that injection of cisplatin at ZT1 caused more severe pathological changes in the kidney than that occurred at ZT13, evidenced by higher serum levels blood urea nitrogen (BUN) and Cr, as well as higher expression levels of Kim-1 and Ngal in the kidney (Supplementary Table 1)
Cisplatin should first be incorporated into renal cells by organic cation transporter 2 (OCT2), and forms DNA adducts, resulting in the activation of apoptotic signals and the renal cell death
Summary
A platinum-based chemotherapeutic agent, has been widely used in the treatment of various solid tumors, including lung, breast, esophageal, ovarian, and pancreatic cancers[1,2,3,4,5]. Despite the efficiency of cisplatin, the undesirable side effects occurring in multiple tissues, especially in the kidney, limit its clinical application[6]. Even though the toxicity of cisplatin remains well recognized, the substitutes of cisplatin fail to satisfactorily meet the clinic demands. Several approaches have been developed to minimize the toxicity of cisplatin, notably including chronotherapy and hydration regimens/supplementation[12,13]. Chronotherapy is defined by the administration of therapeutic agents at the right time, according to the biological rhythms of the host, and has been proven to functionally reduce the renal injury induced by cisplatin
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
