Fluorofenidone protects against acute kidney injury.

Abstract

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.-Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury.

• Authors: YuPeng Jiang, Jiao Quan, Yang Chen, Xiaohua Liao, Qin Dai, Rong Lu, Yue Yu, Gaoyun Hu, Qianbin Li, Jie Meng, Yanyun Xie, Zhangzhe Peng, Lijian Tao
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 12 Pg. 14325-14336 (12 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 31661638 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone
• Antineoplastic Agents
• Copper Transporter 1
• Organic Cation Transporter 2
• Pyridones
• Reactive Oxygen Species
• Peroxidase
• Mitogen-Activated Protein Kinase Kinases
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, prevention & control)
• Animals
• Antineoplastic Agents (toxicity)
• Cell Line
• Cisplatin (toxicity)
• Copper Transporter 1 (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Inflammation (chemically induced, prevention & control)
• Kidney (cytology, drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase Kinases (genetics, metabolism)
• Organic Cation Transporter 2 (genetics, metabolism)
• Peroxidase (metabolism)
• Pyridones (pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species
• Reperfusion Injury