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Nox4 is a Target for Tuberin Deficiency Syndrome
Qian Shi1,2, Suryavathi Viswanadhapalli3, William E Friedrichs3
1Departments of Medicine/Division of Nephrology, University of Texas Health San Antonio, San Antonio, Texas, USA. shiq@uthscsa.edu.
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.
Insights
Tuberous Sclerosis Complex (TSC) involves increased reactive oxygen species (ROS) due to TSC2 gene deficiency. Targeting Nox4, an enzyme linked to ROS production, shows promise for treating TSC-related tumors.
Area of Science:
- Cell Biology
- Oncology
- Genetics
Background:
- The precise mechanisms linking TSC2 gene deficiency to Tuberous Sclerosis Complex (TSC) pathology remain incompletely understood.
- Renal angiomyolipomas in TSC patients and Tsc2+/- mouse kidneys show elevated reactive oxygen species (ROS).
Purpose of the Study:
- To elucidate the role of TSC2 deficiency in ROS production and identify potential therapeutic targets for TSC.
- To investigate the relationship between tuberin, Nox4, and mTORC1 signaling in TSC pathogenesis.
Main Methods:
- Analysis of ROS and Nox4 levels in renal tissues from TSC patients and Tsc2+/- mice.
- In vitro studies using renal proximal tubular epithelial cells with tuberin downregulation.
- Pharmacological inhibition and genetic silencing of mTORC1 pathway components.
- Xenograft models using tuberin-null cells treated with Nox4 inhibitors.
Main Results:
- Tuberin deficiency significantly increased ROS and Nox4 expression in renal tubular cells.
- mTORC1 activation correlated with increased Nox4 and ROS; inhibition of mTORC1 attenuated ROS production.
- Nox4 inhibition, using anti-sense oligonucleotides or GKT137831, significantly reduced tumor growth in vivo.
Conclusions:
- An antagonistic relationship exists between tuberin and Nox4 in driving oncogenesis in tuberin deficiency syndromes.
- Nox4 is identified as a key mediator of ROS production in TSC and a potential therapeutic target for TSC-related diseases.
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