Nox4 is a Target for Tuberin Deficiency Syndrome

Scientific Reports
Qian ShiHanna E Abboud

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 anta...Continue Reading

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Citations

Mar 25, 2019·Cancer Letters·Sankaralingam SaikolappanHari K Koul

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Methods Mentioned

BETA
xenograft
biopsy
flow cytometry
biopsies
xenografts
antisense oligonucleotide
antisense
transfection
protein assay
electrophoresis

Software Mentioned

ImageJ
Tukey
GraphPad Prism
FlowJo
BD
Biosciences Cell Quest

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