Tuberin regulates reactive oxygen species in renal proximal cells, kidney from rodents, and kidney from patients with tuberous sclerosis complex

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 increased oxidative DNA damage in renal cells. In this study, the role of tuberin in the regulating of ROS and NADPH oxidases was investigated. Formation of ROS and activity of NADPH oxidases were significantly higher in mouse embryonic fibroblasts and in primary culture of rat renal proximal tubular epithelial tuberin‐deficient cells compared to wild‐type cells. In addition, expression of NADPH oxidase (Nox)1, Nox2, and Nox4 (Nox isoforms) was higher in mouse embryonic fibroblasts and renal proximal tubular epithelial tuberin‐deficient cells compared to wild‐type cells. Furthermore, activity levels of NADPH oxidases and protein expression of all Nox isoforms were higher in the renal cortex of rat deficient in tuberin. However, treatment of tuberin‐deficient cells with rapamycin showed significant decrease in protein expression of all Nox. Significant increase in protein kinase C βII expression was detected in tuberin‐deficient cells, whereas inhibition of protein kinase C βII by bisindolylmaleimide I resulted in decreased protein expression of all Nox isoforms. In addition, treatment of mice deficient in tuberin with rapamycin resulted in significant decrease in all Nox protein expression. Moreover, protein and mRNA expression of all Nox were highly expressed in tumor kidney tissue of patients with tuberous sclerosis complex compared to control kidney tissue of normal subjects. These data provide the first evidence that tuberin plays a novel role in regulating ROS generation, NADPH oxidase activity, and Nox expression that may potentially be involved in development of kidney tumor in patients with tuberous sclerosis complex.

Heptachlor-induced epithelial to mesenchymal transition in HK-2 cells mediated via TGF-β1/Smad signalling

“…To evaluate the source of ROS in heptachlortreated HK-2 cells, we measured the NOX-4 activity which seems to be primary renal oxidase and has been identified as a source for ROS in renal cells. 26 Our results revealed significant increased activity of NOX-4 in a dose-dependent manner in a heptachlorstimulated HK-2 cells ( Figure 5). Earlier, similar studies also reported that OCPs induced NOX activation in different cell line models.…”

A novel pan-Nox inhibitor, APX-115, protects kidney injury in streptozotocin-induced diabetic mice: possible role of peroxisomal and mitochondrial biogenesis

“…Nox2 is the major Nox isoform responsible for macrophages activation [ 22 ]. Nox2 is expressed also in kidney tissues [ 23 , 24 ] and tubular epithelial cells [ 25 ]. Therefore, targeting all Nox isoforms might be a better strategy against ROS-induced kidney injury in diabetes.…”

Targeted inhibition of endoplasmic reticulum stress: New hope for renal fibrosis

“…Oxidative stress is usually produced by reactive oxygen species (ROS). Oxidative stress is common in CKD and serves an important role in renal fibrosis progression ( 5 ). ROS attack, denature and modify the structure and function of molecules and activate redox-sensitive transcription factors and signaling pathways, resulting in tissue injury and dysfunction.…”

“…ROS attack, denature and modify the structure and function of molecules and activate redox-sensitive transcription factors and signaling pathways, resulting in tissue injury and dysfunction. These events increase ECM expression and promote the development of renal fibrosis ( 5 ).…”

“…Collectively, these changes lead to renal tubule fibrosis, glomerular sclerosis, renal artery stenosis and chronic inflammatory cell infiltration ( 2 ). It is currently believed that renal fibrosis develops in response to ECM accumulation due to epithelial-mesenchymal transition (EMT) ( 3 ), transforming growth factor (TGF)-β signaling ( 4 ), oxidative stress ( 5 ) and proteinuria ( 6 ). Endoplasmic reticulum stress (ERS) is a physiological or pathological condition that can be caused by glucose deprivation, hypoxia or virus infection.…”