Novel mechanism of regulation of fibrosis in kidney tumor with tuberous sclerosis

Liang, Sitai; Cuevas, Gabriela; Tizani, Shaza; Salas, Tiffanie; Liu, Huijuan; Li, Baojie; Habib, Samy L.

doi:10.1186/1476-4598-12-49

Cited by 16 publications

(12 citation statements)

References 30 publications

(29 reference statements)

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“…A unique function of homodimeric ARNT as compared with heterodimeric ARNT is supported by recent studies that established the palindromic E-box motif CACGTG as a critical binding site for ARNT homodimers, while family, which is predominantly known to heterodimerize with other PAS family members to form heterodimeric transcription factors, classically with an α subunit of HIF or the dioxin receptor AHR to mediate hypoxia or xenobiotic responses by targeting correlation between ARNT and FKBP12/YY1 in multiple organ systems, including renal, cardiovascular, and digestive tissues, confirming our findings (GEO GSE3526, Supplemental Table 8) (48). In this context, previous reports implicate activation of a YY1 signaling axis as detectable in renal, cardiac, hepatic, and pulmonary pathologies and show that YY1 depletion protects from chronic organ failure (49)(50)(51).…”

Section: Discussionsupporting

confidence: 89%

Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure

Tampe¹,

Tampe²,

Nyamsuren³

et al. 2018

Journal of Clinical Investigation

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Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein-signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches.

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Section: Discussionsupporting

confidence: 89%

Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure

Tampe¹,

Tampe²,

Nyamsuren³

et al. 2018

Journal of Clinical Investigation

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“…Protein concentration of the cell lysates was determined with the Bradford reagent using BSA as a standard. Western blot analysis was carried out as previously described . Tuberin, p‐p70S6K, and p70S6K antibodies were purchased from Cell Signaling Technology (Danvers, MA).…”

Section: Methodsmentioning

confidence: 99%

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

Habib

Abboud

2016

Cancer Science

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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.

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“…Detection of Ki67 and VEGF was performed on paraffin kidney tumor sections from mice by immunoperoxidase staining as previously described (Liang et al, 2013). Sections were incubated with rabbit anti-Ki67 or VEGF antibody (Abcam, Cambridge, MA, USA) for 30 min, washed twice with PBS, and incubated with horseradish peroxidaselabeled anti-rabbit antibody for 30 min.…”

Section: Immunoperoxidase Staining Of Ki67 and Vegfmentioning

confidence: 99%

Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer

Liang

Medina

et al. 2018

Molecular Oncology

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Loss of Von Hippel‐Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia‐inducible factor (HIF‐α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5‐aminoimidazole‐4‐carboxamide‐riboside (AICAR) as AMPK activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and HIF‐2α expression in renal cell carcinoma cells, including primary cells isolated from kidney cancer patients. Significant decreases in cell migration and invasion were detected using drug combinations. Drug combinations effectively abolished binding of HIF‐2α to the Akt promoter and effected formation of the DNA‐protein complex in nuclear extracts from 786‐O cells, as demonstrated using electromobility shift assay and examination of Akt promoter activity. Importantly, we tested the effect of each drug and the combined drugs on kidney tumor size in the nude mouse model. Our data show that treatment with rapamycin, AICAR, and rapamycin+AICAR decreased tumor size by 38%, 36%, and 80%, respectively, suggesting that drug combinations have an additive effect in reducing tumor size compared with use of each drug alone. Drug combinations effectively decreased cell proliferation, increased apoptotic cells, and significantly decreased p‐Akt, HIF‐2α, and vascular endothelial growth factor expression in tumor kidney tissues from mice. These results show for the first time that drug combinations are more effective than single drugs in reducing kidney tumor progression. This study provides important evidence that may lead to the initiation of pre‐clinical trials in patients with kidney cancer.

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Novel mechanism of regulation of fibrosis in kidney tumor with tuberous sclerosis

Cited by 16 publications

References 30 publications

Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure

Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure

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

Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer

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