β-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis
Ruixue Tian,
Shuqin Tang,
Jingyu Zhao,
Yajie Hao,
Limei Zhao,
Xiutao Han,
Xingru Wang,
Lijun Zhang,
Rongshan Li,
Xiaoshuang Zhou
Affiliations
Ruixue Tian
Department of Nephrology, Shanxi Provincial People’s Hospital; The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China
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 β-hydroxybutyrate (β-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of β-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 β-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 in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of β-HB on cisplatin-induced AKI. Exogenous or endogenous β-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, β-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. β-HB also improved mitochondrial morphology and function. Moreover, β-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that β-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 β-HB. This study provided evidence of the protective effects of β-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.
