Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4
<b>Background/Objectives:</b> Cisplatin nephrotoxicity is a significant clinical issue, and currently, no approved drug exists to prevent cisplatin-induced acute kidney injury (AKI). This study investigated whether sodium phenylbutyrate (4-PBA), a chemical chaperone, can prevent cisplati...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/12/12/2815 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850049375877726208 |
|---|---|
| author | Chang Joo Oh Wooyoung Choi Ha Young Lee In-Kyu Lee Min-Ji Kim Jae-Han Jeon |
| author_facet | Chang Joo Oh Wooyoung Choi Ha Young Lee In-Kyu Lee Min-Ji Kim Jae-Han Jeon |
| author_sort | Chang Joo Oh |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Cisplatin nephrotoxicity is a significant clinical issue, and currently, no approved drug exists to prevent cisplatin-induced acute kidney injury (AKI). This study investigated whether sodium phenylbutyrate (4-PBA), a chemical chaperone, can prevent cisplatin-induced AKI. <b>Methods:</b> Six consecutive days of intraperitoneal injections of 4-PBA were administered in a murine model before and after the cisplatin challenge. This study evaluated tubular injury, serum blood urea nitrogen (BUN) and creatinine levels, and inflammatory markers such as tumor necrosis factor-alpha (TNF-α) and intercellular adhesion molecule 1 (ICAM-1). Additionally, apoptosis, mitochondrial membrane potential, oxygen consumption ratio, and reactive oxygen species (ROS) were assessed in renal tubular cells. The expression levels of pyruvate dehydrogenase kinase 4 (Pdk4) were also analyzed. <b>Results:</b> 4-PBA prevented tubular injury and normalized serum BUN and creatinine levels. Inflammatory markers TNF-α and ICAM-1 were suppressed. In renal tubular cells, 4-PBA reduced apoptosis, restored mitochondrial membrane potential and oxygen consumption ratio, and reduced ROS production. Mechanistically, 4-PBA suppressed the expression of Pdk4, which is known to be induced during cisplatin-induced renal injury. The protective effect of 4-PBA was abolished in Pdk4-overexpressing renal tubular cells, indicating that the efficacy of 4-PBA partially depends on the suppression of Pdk4 expression. In cancer cells, 4-PBA did not interfere with the anti-cancer efficacy of cisplatin. <b>Conclusions:</b> These findings suggest that 4-PBA effectively prevents cisplatin-induced acute kidney injury by suppressing Pdk4. |
| format | Article |
| id | doaj-art-c6e29c1e190f4d7d8bc92307ce07b4e5 |
| institution | DOAJ |
| issn | 2227-9059 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj-art-c6e29c1e190f4d7d8bc92307ce07b4e52025-08-20T02:53:43ZengMDPI AGBiomedicines2227-90592024-12-011212281510.3390/biomedicines12122815Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4Chang Joo Oh0Wooyoung Choi1Ha Young Lee2In-Kyu Lee3Min-Ji Kim4Jae-Han Jeon5Research Institute of Aging and Metabolism, School of Medicine, Kyungpook National University, Daegu 41404, Republic of KoreaDepartment of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of KoreaResearch Institute of Aging and Metabolism, School of Medicine, Kyungpook National University, Daegu 41404, Republic of KoreaResearch Institute of Aging and Metabolism, School of Medicine, Kyungpook National University, Daegu 41404, Republic of KoreaDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Republic of KoreaResearch Institute of Aging and Metabolism, School of Medicine, Kyungpook National University, Daegu 41404, Republic of Korea<b>Background/Objectives:</b> Cisplatin nephrotoxicity is a significant clinical issue, and currently, no approved drug exists to prevent cisplatin-induced acute kidney injury (AKI). This study investigated whether sodium phenylbutyrate (4-PBA), a chemical chaperone, can prevent cisplatin-induced AKI. <b>Methods:</b> Six consecutive days of intraperitoneal injections of 4-PBA were administered in a murine model before and after the cisplatin challenge. This study evaluated tubular injury, serum blood urea nitrogen (BUN) and creatinine levels, and inflammatory markers such as tumor necrosis factor-alpha (TNF-α) and intercellular adhesion molecule 1 (ICAM-1). Additionally, apoptosis, mitochondrial membrane potential, oxygen consumption ratio, and reactive oxygen species (ROS) were assessed in renal tubular cells. The expression levels of pyruvate dehydrogenase kinase 4 (Pdk4) were also analyzed. <b>Results:</b> 4-PBA prevented tubular injury and normalized serum BUN and creatinine levels. Inflammatory markers TNF-α and ICAM-1 were suppressed. In renal tubular cells, 4-PBA reduced apoptosis, restored mitochondrial membrane potential and oxygen consumption ratio, and reduced ROS production. Mechanistically, 4-PBA suppressed the expression of Pdk4, which is known to be induced during cisplatin-induced renal injury. The protective effect of 4-PBA was abolished in Pdk4-overexpressing renal tubular cells, indicating that the efficacy of 4-PBA partially depends on the suppression of Pdk4 expression. In cancer cells, 4-PBA did not interfere with the anti-cancer efficacy of cisplatin. <b>Conclusions:</b> These findings suggest that 4-PBA effectively prevents cisplatin-induced acute kidney injury by suppressing Pdk4.https://www.mdpi.com/2227-9059/12/12/2815cisplatin nephrotoxicityacute kidney injurysodium phenylbutyratepyruvate dehydrogenase kinase 4inflammationapoptosis |
| spellingShingle | Chang Joo Oh Wooyoung Choi Ha Young Lee In-Kyu Lee Min-Ji Kim Jae-Han Jeon Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4 Biomedicines cisplatin nephrotoxicity acute kidney injury sodium phenylbutyrate pyruvate dehydrogenase kinase 4 inflammation apoptosis |
| title | Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4 |
| title_full | Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4 |
| title_fullStr | Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4 |
| title_full_unstemmed | Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4 |
| title_short | Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4 |
| title_sort | sodium phenylbutyrate attenuates cisplatin induced acute kidney injury through inhibition of pyruvate dehydrogenase kinase 4 |
| topic | cisplatin nephrotoxicity acute kidney injury sodium phenylbutyrate pyruvate dehydrogenase kinase 4 inflammation apoptosis |
| url | https://www.mdpi.com/2227-9059/12/12/2815 |
| work_keys_str_mv | AT changjoooh sodiumphenylbutyrateattenuatescisplatininducedacutekidneyinjurythroughinhibitionofpyruvatedehydrogenasekinase4 AT wooyoungchoi sodiumphenylbutyrateattenuatescisplatininducedacutekidneyinjurythroughinhibitionofpyruvatedehydrogenasekinase4 AT hayounglee sodiumphenylbutyrateattenuatescisplatininducedacutekidneyinjurythroughinhibitionofpyruvatedehydrogenasekinase4 AT inkyulee sodiumphenylbutyrateattenuatescisplatininducedacutekidneyinjurythroughinhibitionofpyruvatedehydrogenasekinase4 AT minjikim sodiumphenylbutyrateattenuatescisplatininducedacutekidneyinjurythroughinhibitionofpyruvatedehydrogenasekinase4 AT jaehanjeon sodiumphenylbutyrateattenuatescisplatininducedacutekidneyinjurythroughinhibitionofpyruvatedehydrogenasekinase4 |