Tuberin Regulates Reactive Oxygen Species in Renal Proximal Cells, Kidney from Rodents and Kidney from TSC Patients

Abstract

Reactive oxygen species (ROS) are an important endogenous source of DNA damage and oxidative stress in all cell types. Deficiency in tuberin resulted in increase oxidative DNA damage in renal cells. In this study, role of tuberin in the regulating of ROS and NAD(PH)oxidases was investigated. ROS formation and NAD(P)H oxidases activity were significantly higher in mouse embryonic fibroblasts (MEF) and in primary culture of rat renal proximal tubular epithelial (RPTE) tuberin-deficient cells compared to wild type cells. In addition, Nox1, Nox2 and Nox4 (Nox isoforms) expression was higher in MEF and RPTE tuberin-deficient cells compared to wild type cells. Furthermore, NAD(P)H oxidases activity levels and protein expression of all Nox isoforms were higher in the renal cortex of rat deficient in tuberin. On the other hand, treatment of tuberin-deficient cells with rapamycin showed significant decrease in protein expression of all Noxs. Significant increase in PKCβII expression was detected in tuberin-deficient cells while inhibition of PKCβII by BMI resulted in decrease all Noxs protein expression. In addition, treatment of mice-deficient in tuberin with rapamycin resulted in significant decrease in all Noxs protein expression. Moreover, protein and mRNA expression of all Noxs were highly expressed in tumor kidney tissue of TSC patients compared to control kidney tissue of normal subjects. These data provide the first evidence that tuberin plays a novel role in regulating ROS generation, NAD(P)H oxidases activity and Noxs expression that may potentially involved in development of kidney tumor in TSC patients.

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