β-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis

• Published in: Renal failure 2024-12, Vol.46 (1), p.2354918-2354918
• Main Authors: Tian, Ruixue, Tang, Shuqin, Zhao, Jingyu, Hao, Yajie, Zhao, Limei, Han, Xiutao, Wang, Xingru, Zhang, Lijun, Li, Rongshan, Zhou, Xiaoshuang
• Format: Article
• Language: English
• Subjects: 3-Hydroxybutyric Acid - pharmacology; Acute Kidney Injury; Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - toxicity; Antineoplastic drugs; Biomarkers; Blood Urea Nitrogen; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Calmodulin; Camkk2; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - toxicity; Creatinine; Creatinine - blood; Cytology; Disease Models, Animal; Ferroptosis; Ferroptosis - drug effects; High fat diet; Humans; Ketogenesis; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidneys; Low carbohydrate diet; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; Molecular modelling; Morphology; nephrotoxicity; Signal Transduction - drug effects; Western blotting; β-hydroxybutyrate
• ISSN: 0886-022X; 1525-6049
• DOI: 10.1080/0886022X.2024.2354918

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 and 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 . 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 . 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.