Deletion of Angiotensin-Converting Enzyme-2 Promotes Hypertensive Nephropathy by Targeting Smad7 for Ubiquitin Degradation

Liu, Zhen; Huang, Xiao-Ru; Chen, Hai-Yong; Fung, Erik; Liu, Jian; Lan, Hui Y.

doi:10.1161/hypertensionaha.117.09600

Cited by 36 publications

(35 citation statements)

References 45 publications

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“…TGF-β1 mediated progressive renal fibrosis by stimulating production and suppressing degradation of ECM [12]. It has been demonstrated that angiotensin II stimulated expression of TGF-β1 and its receptors [39]. Myofibroblasts were a predominant source for ECM production and myofibroblasts activation was the key step in renal fibrosis.…”

Section: Tgf-β/smad Signaling Pathway In Renal Fibrosismentioning

confidence: 99%

New insights into TGF-β/Smad signaling in tissue fibrosis

Chen

Wang

et al. 2018

Chemico-Biological Interactions

510

338

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Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-β/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-β/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-β/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis.

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Section: Tgf-β/smad Signaling Pathway In Renal Fibrosismentioning

confidence: 99%

New insights into TGF-β/Smad signaling in tissue fibrosis

Chen

Wang

et al. 2018

Chemico-Biological Interactions

510

338

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“…TGF-β1 expression is stimulated by glomerular stretch and hyperglycemia in early stage, and by angiotensin II, platelet-derived growth factor (PDGF) and advanced glycation end-product (AGE) in later stages of the disease [40]. Angiotensin II has been demonstrated to raise expression of TGF-β1 and its receptors [41,42]. Unlike CKD, the role of TGF-β1 in acute kidney injury is not completely understood [43].…”

Section: Activation Of Tgf-β1 and Its Role In Renal Fibrosis And Inflmentioning

confidence: 99%

“…Moreover, TGF-β1 promotes renal fibrosis through the cell-cell interaction as TGF-β1 released from the injured epithelium can activate pericyte-myofibroblast transition [57]. In addition, AGE and angiotensin II can activate Smad3 to mediate the hypertension-and diabetes-induced EMT [41,58,59].…”

Section: Tgf-β1 Signaling and Its Role In Myofibroblasts Transdifferementioning

confidence: 99%

“…Extensive studies have identified Smad2 and Smad3 as two major downstream mediators of the biological actions of TGF-β1. In the context of renal fibrosis, Smad2 and Smad3 are activated in both humans and experimental animals with CKD of diverse etiologies including hypertensive nephropathy [41,60,61], remnant kidney disease [54,62], obstructive kidney disease [63], diabetic nephropathy [59,64,65], chronic renal allograft injury [66] and drug-associated nephropathy [67]. Many fibrogenic genes including plasminogen activator inhibitor-1, proteoglycans, integrins, connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase-1 as well as collagens such as collagen type 1 α 1 (Col1α1), collagen type 1 α 2 (Col1α2), collagen type 5 α 2 (Col5α2), collagen type 6 α 1 (Col6α1) and collagen type 6 α 3 (Col6α3) have been shown to be the downstream targets of TGF-β/Smad3 signaling [68].…”

Section: Role Of R-smads (Smad2 and Smad3) In Renal Fibrosis And Emtmentioning

confidence: 99%

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

Chen

Yang

et al. 2018

Biomedicine & Pharmacotherapy

207

161

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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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“…renal fibrosis in mouse models of kidney disease including aristolochic acid nephropathy, hypertensive nephropathy and acute kidney disease (Dai et al 2015;Fu et al 2017;Liu et al 2017). Smad3-specific inhibitors, e.g.…”

Section: Controversy Of Targeting Tgf-β1/smad Signallingmentioning

confidence: 99%

Transforming growth factor-β signalling in renal fibrosis: from Smads to non-coding RNAs

et al. 2018

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Transforming growth factor-β (TGF-β) is the key player in tissue fibrosis. However, antifibrotic therapy targeting this multifunctional protein may interfere with other physiological processes to cause side effects. Thus, precise therapeutic targets need to be identified by further understanding the underlying mechanisms of TGF-β1 signalling during fibrogenesis. Equilibrium of Smad signalling is crucial for TGF-β-mediated renal fibrosis, where Smad3 is pathogenic but Smad2 and Smad7 are protective. The activation of TGF-β1/Smad signalling triggers extracellular matrix deposition, and local myofibroblast generation and activation. Mechanistic studies have shown that TGF-β/Smad3 transits the microRNA profile from antifibrotic to profibrotic and therefore promotes renal fibrosis via regulating non-coding RNAs at transcriptional levels. More importantly, disease-specific Smad3-dependent long non-coding RNAs have been recently uncovered from mouse kidney disease models and may represent novel precision therapeutic targets for chronic kidney disease. In this review, mechanisms of TGF-β-driven renal fibrosis via non-coding RNAs and their translational capacities will be discussed in detail.

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Deletion of Angiotensin-Converting Enzyme-2 Promotes Hypertensive Nephropathy by Targeting Smad7 for Ubiquitin Degradation

Cited by 36 publications

References 45 publications

New insights into TGF-β/Smad signaling in tissue fibrosis

New insights into TGF-β/Smad signaling in tissue fibrosis

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

Transforming growth factor-β signalling in renal fibrosis: from Smads to non-coding RNAs

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