Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury
Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated...
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MDPI AG
2020-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/11/4099 |
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| author | Yizhen Sang Kenji Tsuji Akiko Inoue-Torii Kazuhiko Fukushima Shinji Kitamura Jun Wada |
| author_facet | Yizhen Sang Kenji Tsuji Akiko Inoue-Torii Kazuhiko Fukushima Shinji Kitamura Jun Wada |
| author_sort | Yizhen Sang |
| collection | DOAJ |
| description | Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury. |
| first_indexed | 2024-03-10T19:17:56Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
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| spelling | doaj.art-6a9ec0a166b143b699b3858b6ac1bcaf2023-11-20T03:14:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-012111409910.3390/ijms21114099Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte InjuryYizhen Sang0Kenji Tsuji1Akiko Inoue-Torii2Kazuhiko Fukushima3Shinji Kitamura4Jun Wada5Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanPodocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.https://www.mdpi.com/1422-0067/21/11/4099semaphorin3Apodocyteproteinuriaapoptosisc-Jun N-terminal kinase |
| spellingShingle | Yizhen Sang Kenji Tsuji Akiko Inoue-Torii Kazuhiko Fukushima Shinji Kitamura Jun Wada Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury International Journal of Molecular Sciences semaphorin3A podocyte proteinuria apoptosis c-Jun N-terminal kinase |
| title | Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury |
| title_full | Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury |
| title_fullStr | Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury |
| title_full_unstemmed | Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury |
| title_short | Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury |
| title_sort | semaphorin3a inhibitor ameliorates doxorubicin induced podocyte injury |
| topic | semaphorin3A podocyte proteinuria apoptosis c-Jun N-terminal kinase |
| url | https://www.mdpi.com/1422-0067/21/11/4099 |
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