Ruixue Tian: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China. ORCID
Shuqin Tang: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China.
Jingyu Zhao: The Third Clinical Medical College, Shanxi University of Chinese Medicine, Jinzhong, China.
Yajie Hao: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China.
Limei Zhao: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China.
Xiutao Han: The Third Clinical Medical College, Shanxi University of Chinese Medicine, Jinzhong, China.
Xingru Wang: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China.
Lijun Zhang: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China.
Rongshan Li: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University; Shanxi Kidney Disease Institute, Taiyuan, China.
Xiaoshuang Zhou: Department of Nephrology, Shanxi Provincial People's Hospital; The Fifth Clinical Medical College of Shanxi Medical University; Shanxi Kidney Disease Institute, Taiyuan, China.
Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that ��-hydroxybutyrate (��-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of ��-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or ��-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted and experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of ��-HB on cisplatin-induced AKI. Exogenous or endogenous ��-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis . Additionally, ��-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. ��-HB also improved mitochondrial morphology and function. Moreover, ��-HB significantly attenuated cisplatin-induced cell ferroptosis and damage . Furthermore, western blotting and immunohistochemical staining indicated that ��-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by ��-HB. This study provided evidence of the protective effects of ��-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.
