Nox4 is a Target for Tuberin Deficiency Syndrome
Abstract The mechanism by which TSC2 inactivation or deficiency contributes to the pathology of tuberous sclerosis complex (TSC) is not fully clear. We show that renal angiomyolipomas from TSC patients and kidney cortex from Tsc2+/− mice exhibit elevated levels of reactive oxygen species (ROS). Down...
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Nature Portfolio
2018
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oai:doaj.org-article:018f1020b99449f2ac6f80d207d451232021-12-02T15:08:35ZNox4 is a Target for Tuberin Deficiency Syndrome10.1038/s41598-018-21838-42045-2322https://doaj.org/article/018f1020b99449f2ac6f80d207d451232018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21838-4https://doaj.org/toc/2045-2322Abstract The mechanism by which TSC2 inactivation or deficiency contributes to the pathology of tuberous sclerosis complex (TSC) is not fully clear. We show that renal angiomyolipomas from TSC patients and kidney cortex from Tsc2+/− mice exhibit elevated levels of reactive oxygen species (ROS). Downregulation of tuberin (protein encoded by TSC2 gene) in renal proximal tubular epithelial cells significantly increased ROS concomitant with enhanced Nox4. Similarly, we found elevated levels of Nox4 in the renal cortex of Tsc2+/− mice and in the renal angiomyolipomas from TSC patients. Tuberin deficiency is associated with activation of mTORC1. Rapamycin, shRNAs targeting raptor, or inhibition of S6 kinase significantly inhibited the expression of Nox4, resulting in attenuation of production of ROS in tuberin-downregulated proximal tubular epithelial cells. In contrast, activation of mTORC1 increased Nox4 and ROS. These results indicate that Nox4 may be a potential target for tuberin-deficiency-derived diseases. Using a xenograft model from tuberin-null tubular cells in nude mice, both anti-sense Nox4 and GKT137831, a specific inhibitor of Nox1/4, significantly inhibited the tumor growth. Thus, our results demonstrate the presence of an antagonistic relationship between tuberin and Nox4 to drive oncogenesis in the tuberin deficiency syndrome and identify Nox4 as a target to develop a therapy for TSC.Qian ShiSuryavathi ViswanadhapalliWilliam E. FriedrichsChakradhar VelagapudiCédric SzyndralewiezShweta BansalManzoor A. BhatGoutam Ghosh ChoudhuryHanna E. AbboudNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018) |
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Medicine R Science Q |
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Medicine R Science Q Qian Shi Suryavathi Viswanadhapalli William E. Friedrichs Chakradhar Velagapudi Cédric Szyndralewiez Shweta Bansal Manzoor A. Bhat Goutam Ghosh Choudhury Hanna E. Abboud Nox4 is a Target for Tuberin Deficiency Syndrome |
| description |
Abstract The mechanism by which TSC2 inactivation or deficiency contributes to the pathology of tuberous sclerosis complex (TSC) is not fully clear. We show that renal angiomyolipomas from TSC patients and kidney cortex from Tsc2+/− mice exhibit elevated levels of reactive oxygen species (ROS). Downregulation of tuberin (protein encoded by TSC2 gene) in renal proximal tubular epithelial cells significantly increased ROS concomitant with enhanced Nox4. Similarly, we found elevated levels of Nox4 in the renal cortex of Tsc2+/− mice and in the renal angiomyolipomas from TSC patients. Tuberin deficiency is associated with activation of mTORC1. Rapamycin, shRNAs targeting raptor, or inhibition of S6 kinase significantly inhibited the expression of Nox4, resulting in attenuation of production of ROS in tuberin-downregulated proximal tubular epithelial cells. In contrast, activation of mTORC1 increased Nox4 and ROS. These results indicate that Nox4 may be a potential target for tuberin-deficiency-derived diseases. Using a xenograft model from tuberin-null tubular cells in nude mice, both anti-sense Nox4 and GKT137831, a specific inhibitor of Nox1/4, significantly inhibited the tumor growth. Thus, our results demonstrate the presence of an antagonistic relationship between tuberin and Nox4 to drive oncogenesis in the tuberin deficiency syndrome and identify Nox4 as a target to develop a therapy for TSC. |
| format |
article |
| author |
Qian Shi Suryavathi Viswanadhapalli William E. Friedrichs Chakradhar Velagapudi Cédric Szyndralewiez Shweta Bansal Manzoor A. Bhat Goutam Ghosh Choudhury Hanna E. Abboud |
| author_facet |
Qian Shi Suryavathi Viswanadhapalli William E. Friedrichs Chakradhar Velagapudi Cédric Szyndralewiez Shweta Bansal Manzoor A. Bhat Goutam Ghosh Choudhury Hanna E. Abboud |
| author_sort |
Qian Shi |
| title |
Nox4 is a Target for Tuberin Deficiency Syndrome |
| title_short |
Nox4 is a Target for Tuberin Deficiency Syndrome |
| title_full |
Nox4 is a Target for Tuberin Deficiency Syndrome |
| title_fullStr |
Nox4 is a Target for Tuberin Deficiency Syndrome |
| title_full_unstemmed |
Nox4 is a Target for Tuberin Deficiency Syndrome |
| title_sort |
nox4 is a target for tuberin deficiency syndrome |
| publisher |
Nature Portfolio |
| publishDate |
2018 |
| url |
https://doaj.org/article/018f1020b99449f2ac6f80d207d45123 |
| work_keys_str_mv |
AT qianshi nox4isatargetfortuberindeficiencysyndrome AT suryavathiviswanadhapalli nox4isatargetfortuberindeficiencysyndrome AT williamefriedrichs nox4isatargetfortuberindeficiencysyndrome AT chakradharvelagapudi nox4isatargetfortuberindeficiencysyndrome AT cedricszyndralewiez nox4isatargetfortuberindeficiencysyndrome AT shwetabansal nox4isatargetfortuberindeficiencysyndrome AT manzoorabhat nox4isatargetfortuberindeficiencysyndrome AT goutamghoshchoudhury nox4isatargetfortuberindeficiencysyndrome AT hannaeabboud nox4isatargetfortuberindeficiencysyndrome |
| _version_ |
1718388039417331712 |