Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model
Abstract Background Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study,...
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | BMC Pharmacology and Toxicology |
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| Online Access: | http://link.springer.com/article/10.1186/s40360-020-00432-3 |
| _version_ | 1828893694107844608 |
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| author | Shinya Morita Kazunobu Shinoda Tadashi Yoshida Masayuki Shimoda Yoshihiko Kanno Ryuichi Mizuno Hidaka Kono Hiroshi Asanuma Ken Nakagawa Kazuo Umezawa Mototsugu Oya |
| author_facet | Shinya Morita Kazunobu Shinoda Tadashi Yoshida Masayuki Shimoda Yoshihiko Kanno Ryuichi Mizuno Hidaka Kono Hiroshi Asanuma Ken Nakagawa Kazuo Umezawa Mototsugu Oya |
| author_sort | Shinya Morita |
| collection | DOAJ |
| description | Abstract Background Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. Methods We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. Results DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue. Conclusions These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity. |
| first_indexed | 2024-12-13T13:57:42Z |
| format | Article |
| id | doaj.art-04b3e50267d7475d8aa42171c1735839 |
| institution | Directory Open Access Journal |
| issn | 2050-6511 |
| language | English |
| last_indexed | 2024-12-13T13:57:42Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
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| series | BMC Pharmacology and Toxicology |
| spelling | doaj.art-04b3e50267d7475d8aa42171c17358392022-12-21T23:42:50ZengBMCBMC Pharmacology and Toxicology2050-65112020-08-0121111210.1186/s40360-020-00432-3Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat modelShinya Morita0Kazunobu Shinoda1Tadashi Yoshida2Masayuki Shimoda3Yoshihiko Kanno4Ryuichi Mizuno5Hidaka Kono6Hiroshi Asanuma7Ken Nakagawa8Kazuo Umezawa9Mototsugu Oya10Department of Urology, Keio University School of MedicineDepartment of Urology, Keio University School of MedicineApheresis and Dialysis Center, Keio University School of MedicineDepartment of Pathology, Keio University School of MedicineDepartment of Nephrology, Tokyo Medical UniversityDepartment of Urology, Keio University School of MedicineDepartment of Urology, Tokyo Dental College Ichikawa General HospitalDepartment of Urology, Keio University School of MedicineDepartment of Urology, Tokyo Dental College Ichikawa General HospitalDepartment of Molecular Target Medicine Screening, Aichi Medical UniversityDepartment of Urology, Keio University School of MedicineAbstract Background Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. Methods We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. Results DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue. Conclusions These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.http://link.springer.com/article/10.1186/s40360-020-00432-3CyclosporineNephrotoxicityNF-κBNF-κB inhibitor |
| spellingShingle | Shinya Morita Kazunobu Shinoda Tadashi Yoshida Masayuki Shimoda Yoshihiko Kanno Ryuichi Mizuno Hidaka Kono Hiroshi Asanuma Ken Nakagawa Kazuo Umezawa Mototsugu Oya Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model BMC Pharmacology and Toxicology Cyclosporine Nephrotoxicity NF-κB NF-κB inhibitor |
| title | Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model |
| title_full | Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model |
| title_fullStr | Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model |
| title_full_unstemmed | Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model |
| title_short | Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model |
| title_sort | dehydroxymethylepoxyquinomicin a novel nuclear factor κb inhibitor prevents the development of cyclosporine a nephrotoxicity in a rat model |
| topic | Cyclosporine Nephrotoxicity NF-κB NF-κB inhibitor |
| url | http://link.springer.com/article/10.1186/s40360-020-00432-3 |
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