Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy

Liu, Zhen; Huang, Xiao‐Ru; Chen, Haiyong; Penninger, Josef; Lan, Hui‐Yao

doi:10.1038/labinvest.2012.2

Cited by 105 publications

(90 citation statements)

References 42 publications

(71 reference statements)

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“…34,35 In progressive fibrogenesis, these two pathways amplify each other to drive inflammation and fibrosis. [36][37][38][39] Here, we show that both NFkB and Smad signaling were induced in damaged REPs. By using pharmacologic activators of each signaling type, we clarified differential roles of these two signaling pathways. NFkB signaling is responsible for the rapid repression of Epoproducing potential, whereas Smad signaling is more related to the fibrogenic activity.…”

Section: Discussionmentioning

confidence: 60%

“…19 However, the fact that not all of the IKK2ca-overexpressed REPs changed into myofibroblasts implies the requirement of other coinsulting signals that might synergize with the NFkB pathway. [34][35][36][37][38][39] There are growing numbers of clinical and experimental reports suggesting that structural damage of the kidney, including fibrosis, can be reversible. [40][41][42][43][44] Therefore, elucidating whether diseased REPs in ESRD can be reversed to their physiologically normal state is an important lingering issue.…”

Section: Discussionmentioning

confidence: 99%

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Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

Souma¹,

Yamazaki²,

Moriguchi³

et al. 2013

Journal of the American Society of Nephrology

159

223

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CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFkB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFkB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFkB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

Souma¹,

Yamazaki²,

Moriguchi³

et al. 2013

Journal of the American Society of Nephrology

159

223

View full text Add to dashboard Cite

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“…The contribution of Ang II to the progression of renal pathology has been elegantly illustrated by genetic studies using angiotensin-converting enzyme 2 (ACE-2) knockout mice (Zhong et al, 2011;Liu et al, 2012) and by pharmacologic studies using ACE inhibitors and Ang II-receptor blockers (Ishidoya et al, 1995;Ruiz-Ortega et al, 1995;Taal and Brenner, 2000). The fibrogenic effects of Ang II are attributed to its activation of transforming growth factor-b (TGF-b) signaling (Coresh et al, 2007), the essential signaling pathway involved in extracellular matrix deposition and tissue homeostasis and repair.…”

Section: Introductionmentioning

confidence: 99%

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

Qian

Peng

Qiu

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Chronic activation of renin-angiotensin system (RAS) greatly contributes to renal fibrosis and accelerates the progression of chronic kidney disease; however, the underlying molecular mechanism is poorly understood. Angiotensin II (Ang II), the central component of RAS, is a key regulator of renal fibrogenic destruction. Here we show that epidermal growth factor receptor (EGFR) plays an important role in Ang II-induced renal fibrosis. Inhibition of EGFR activation by novel small molecules or by short hairpin RNA knockdown in Ang II-treated SV40 mesangial cells in vitro suppresses protein kinase B and extracellular signal-related kinase signaling pathways and transforming growth factor-b/Sma-and Mad-related protein activation, and abolishes the accumulation of fibrotic markers such as connective tissue growth factor, collagen IV. The transactivation of EGFR by Ang II in SV40 cells depends on the phosphorylation of proto-oncogene tyrosine-protein kinase Src (c-Src) kinase. Further validation in vivo demonstrates that EGFR small molecule inhibitor successfully attenuates renal fibrosis and kidney dysfunction in a mouse model induced by Ang II infusion. These findings indicate a crucial role of EGFR in Ang II-dependent renal deterioration, and reveal EGFR inhibition as a new therapeutic strategy for preventing progression of chronic renal diseases.

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“…In addition, Smads also interact with other signaling pathways, including NF-κB pathways (19,41). Liu et al (42) found that TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation were involved in a mouse model of obstructive nephropathy. Ka et al (24) demonstrated that the TGF-β/Smad and NF-κB signaling pathways were inhibited during therapy for type Ⅱ DN.…”

Section: Discussionmentioning

confidence: 99%

Role of the TGFβ/p65 pathway in tanshinone IIA-treated HBZY-1 cells

Chen

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract. Tanshinone ⅡA (TⅡA) is widely used for the treatment of a number human diseases, including diabetic nephropathy (DN) (1). The present study was performed to examine the role of the transforming growth factor β (TGFβ)/p65 pathway under TⅡA treatment in a glomerular mesangial cell model of DN. Firstly, it was identified that TⅡA inhibited the proliferation of HBZY-1 cells, while simultaneously suppressing the expression of TGFβ and p65. In addition, glucose-induced HBZY-1 cells were treated with TⅡA, si-TGFβ and si-p65. The results revealed that si-TGFβ or si-p65 were able to inhibit the proliferation of HBZY-1 cells as well. Finally, the expression of TGFβ and p65 in a rat model of DN treated with TⅡA was detected. The results demonstrated that renal hypertrophy and 24 h urinary protein excretion were ameliorated in TⅡA-treated rats with DN. Furthermore, it was revealed that the protein levels of TGFβ and p65 were decreased in the DN rats following TⅡA treatment. In conclusion, the present study demonstrated that TGFβ and p65 were activated by TⅡA in HBZY-1 cells. In addition, the expression of TGFβ and of p65 was downregulated in rats with DN treated with TⅡA.

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Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy

Cited by 105 publications

References 42 publications

Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

Role of the TGFβ/p65 pathway in tanshinone IIA-treated HBZY-1 cells

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