c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury
Aristolochic acid (AA) is a toxin that induces DNA damage in tubular epithelial cells of the kidney and is the cause of Balkan Nephropathy and Chinese Herb Nephropathy. In cultured tubular epithelial cells, AA induces a pro-fibrotic response via the c-Jun amino terminal kinase (JNK) signaling pathwa...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.599114/full |
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| author | Fan Yang Fan Yang Elyce Ozols Frank Y. Ma Khai Gene Leong Greg H. Tesch Xiaoyun Jiang David J. Nikolic-Paterson |
| author_facet | Fan Yang Fan Yang Elyce Ozols Frank Y. Ma Khai Gene Leong Greg H. Tesch Xiaoyun Jiang David J. Nikolic-Paterson |
| author_sort | Fan Yang |
| collection | DOAJ |
| description | Aristolochic acid (AA) is a toxin that induces DNA damage in tubular epithelial cells of the kidney and is the cause of Balkan Nephropathy and Chinese Herb Nephropathy. In cultured tubular epithelial cells, AA induces a pro-fibrotic response via the c-Jun amino terminal kinase (JNK) signaling pathway. This study investigated the in vivo role of JNK signaling with a JNK inhibitor (CC-930) in mouse models of acute high dose AA-induced kidney injury (day 3) and renal fibrosis induced by chronic low dose AA exposure (day 22). CC-930 treatment inhibited JNK signaling and protected from acute AA-induced renal function impairment and severe tubular cell damage on day 3, with reduced macrophage infiltration and expression of pro-inflammatory molecules. In the chronic model, CC-930 treatment inhibited JNK signaling but did not affect AA-induced renal function impairment, tubular cell damage including the DNA damage response and induction of senescence, or renal fibrosis; despite a reduction in the macrophage pro-inflammatory response. In conclusion, JNK signaling contributes to acute high dose AA-induced tubular cell damage, presumably via an oxidative stress-dependent mechanism, but is not involved in tubular atrophy and senescence that promote chronic kidney disease caused by ongoing DNA damage in chronic low dose AA exposure. |
| first_indexed | 2024-04-11T04:36:57Z |
| format | Article |
| id | doaj.art-7e134452bf7a4335884514e7c2558e8d |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-11T04:36:57Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-7e134452bf7a4335884514e7c2558e8d2022-12-28T09:09:34ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-02-011210.3389/fphys.2021.599114599114c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney InjuryFan Yang0Fan Yang1Elyce Ozols2Frank Y. Ma3Khai Gene Leong4Greg H. Tesch5Xiaoyun Jiang6David J. Nikolic-Paterson7Department of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, AustraliaDepartment of Pediatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, AustraliaDepartment of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, AustraliaDepartment of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, AustraliaDepartment of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, AustraliaDepartment of Pediatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, AustraliaAristolochic acid (AA) is a toxin that induces DNA damage in tubular epithelial cells of the kidney and is the cause of Balkan Nephropathy and Chinese Herb Nephropathy. In cultured tubular epithelial cells, AA induces a pro-fibrotic response via the c-Jun amino terminal kinase (JNK) signaling pathway. This study investigated the in vivo role of JNK signaling with a JNK inhibitor (CC-930) in mouse models of acute high dose AA-induced kidney injury (day 3) and renal fibrosis induced by chronic low dose AA exposure (day 22). CC-930 treatment inhibited JNK signaling and protected from acute AA-induced renal function impairment and severe tubular cell damage on day 3, with reduced macrophage infiltration and expression of pro-inflammatory molecules. In the chronic model, CC-930 treatment inhibited JNK signaling but did not affect AA-induced renal function impairment, tubular cell damage including the DNA damage response and induction of senescence, or renal fibrosis; despite a reduction in the macrophage pro-inflammatory response. In conclusion, JNK signaling contributes to acute high dose AA-induced tubular cell damage, presumably via an oxidative stress-dependent mechanism, but is not involved in tubular atrophy and senescence that promote chronic kidney disease caused by ongoing DNA damage in chronic low dose AA exposure.https://www.frontiersin.org/articles/10.3389/fphys.2021.599114/fullacute kidney injurychronic kidney diseaseinflammationc-Jun amino terminal kinasemacrophagerenal fibrosis |
| spellingShingle | Fan Yang Fan Yang Elyce Ozols Frank Y. Ma Khai Gene Leong Greg H. Tesch Xiaoyun Jiang David J. Nikolic-Paterson c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury Frontiers in Physiology acute kidney injury chronic kidney disease inflammation c-Jun amino terminal kinase macrophage renal fibrosis |
| title | c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury |
| title_full | c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury |
| title_fullStr | c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury |
| title_full_unstemmed | c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury |
| title_short | c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury |
| title_sort | c jun amino terminal kinase signaling promotes aristolochic acid induced acute kidney injury |
| topic | acute kidney injury chronic kidney disease inflammation c-Jun amino terminal kinase macrophage renal fibrosis |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.599114/full |
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