Molecular mechanism of smurf2 in regulating the expression of SnoN in diabetic nephropathy

Xu, Zhou; Diao, Zongli; Liu, Ruixia; Liu, Wenhu

doi:10.3892/mmr.2017.6307

Cited by 14 publications

(10 citation statements)

References 20 publications

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“…Smurf2 also promotes the TGF-β/Smad signaling functions by enhancing degradation of TGFβR and Smad2, leading to reduction of biological function of TGF-β1 [141]. The TGF-β/Smad downregulate expression and heightens degradation of SnoN by smurf2 in diabetic nephrology [143]. Similarly, SnoN protein level is reduced while its mRNA level is increased and protein and mRNA levels of Smurf2 are increased in the human renal proximal tubule epithelial cells (hRPTEC) exposed to high glucose concentrations.…”

Section: Post-translational Regulation Of Tgf-β/smad Signaling By Ubimentioning

confidence: 99%

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Chen

Yang

et al. 2018

Biomedicine & Pharmacotherapy

277

200

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Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-β1 (TGF-β1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF-β1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-β1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-β1. The Smad signaling system plays a central role in regulation of TGF-β1 and TGF-β/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-β/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF-β1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-β-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF-κB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-κB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-β1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD.

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Section: Post-translational Regulation Of Tgf-β/smad Signaling By Ubimentioning

confidence: 99%

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Chen

Yang

et al. 2018

Biomedicine & Pharmacotherapy

277

200

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“… 236 It is clear that the polyubiquitination and degradation of SnoN via Smurf2 induced by the TGF-β/Smad pathway is critical in diabetic nephropathy. 237 BMP7 enhances the levels of SnoN mRNA and protein, which is important for controlling diabetic nephropathy and renal fibrosis. 113 Moreover, the upregulation of SnoN inhibits EMT and renal fibrogenesis induced by high glucose.…”

Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Tecalco-Cruz

Ríos-López

Vázquez‐Victorio

et al. 2018

Sig Transduct Target Ther

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The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis. The TGF-β signaling pathway outcome relies on the control of the spatial and temporal expression of >500 genes, which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway, such as transcriptional factors and cofactors. Ski (Sloan-Kettering Institute) and SnoN (Ski novel) are Smad-interacting proteins that negatively regulate the TGF-β signaling pathway by disrupting the formation of R-Smad/Smad4 complexes, as well as by inhibiting Smad association with the p300/CBP coactivators. The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription. The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms. Thus, these cross-regulatory processes finely modify the TGF-β signaling outcome as they control the magnitude and duration of the TGF-β signals. As a result, any alteration in these regulatory mechanisms may lead to disease development. Therefore, the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-β pathway, such as Ski and SnoN, is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated, such as fibrosis and cancer.

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“…Fructose metabolism leads to increased intracellular uric acid (UA) synthesis [25]. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme stimulate by UA and causing increased intracellular oxidative stress, endothelial injury, RAS activation, increased epithelial-mesenchymal transition mitochondrial injury and adenosine triphosphate depletion [26]. Human glomerular MCs express NADPH oxidase and activates protein kinase C, mitogen activated protein kinase, and nuclear factor-jB (NF-jB) which eventually results in overproduction of extracellular matrix proteins [27].…”

Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy an Obvious Complication in Long Term Type 1 Diabetes Mellitus: A Case Study

Mohammad

Chigurupati

Othman

et al. 2017

Asian J Pharm Clin Res

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Most overwhelming complications of Type 1 diabetes mellitus patients are responsible for complications related to the microvascular system most likely with kidney. In the kidney, hyperglycemia induced microangiopathy resulting not only thickening of the glomerular capillary basement membrane but also to the proliferation of the mesangial matrix and solidifying of the tubular basement membrane. Several biochemical and pathological, factors are concerned for the development of diabetic renal microangiopathy. These include the glomerular hyperperfusion and hyperfiltration, transformed morphology of podocytes accompanies these basement membrane modifications, Type IV collagen augmented synthesis following the hyperglycemia, and increased expression of tissue matrix metalloproteinase. The aim of this case review is to highlight the recent advances in understanding the pathogenesis, diagnosis, the overview and the potential renoprotective therapeutic agents that would prevent the development or the progression of diabetic nephropathy.

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Molecular mechanism of smurf2 in regulating the expression of SnoN in diabetic nephropathy

Cited by 14 publications

References 20 publications

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Diabetic Nephropathy an Obvious Complication in Long Term Type 1 Diabetes Mellitus: A Case Study

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