Signaling by ALK5 mediates TGF-β-induced ET-1 expression in endothelial cells: a role for migration and proliferation

TGF-β1 contributes to chronic kidney disease, at least in part, via Smad3. TGF-β1 is induced in the kidney following acute ischemia, and there is increasing evidence that TGF-β1 may protect against acute kidney injury. As there is a paucity of information regarding the functional significance of Smad3 in acute kidney injury, the present study explored this issue in a murine model of ischemic acute kidney injury in Smad3+/+ and Smad3−/− mice. We demonstrate that, at 24 h after ischemia, Smad3 is significantly induced in Smad3+/+ mice, whereas Smad3−/− mice fail to express this protein in the kidney in either the sham or postischemic groups. Compared with Smad3+/+ mice, and 24 h following ischemia, Smad3−/− mice exhibited greater preservation of renal function as measured by blood urea nitrogen (BUN) and serum creatinine; less histological injury assessed by both semiquantitative and qualitative analyses; markedly suppressed renal expression of IL-6 and endothelin-1 mRNA (but comparable expression of MCP-1, TNF-α, and heme oxygenase-1 mRNA); and no increase in plasma IL-6 levels, the latter increasing approximately sixfold in postischemic Smad3+/+ mice. We conclude that genetic deficiency of Smad3 confers structural and functional protection against acute ischemic injury to the kidney. We speculate that these effects may be mediated through suppression of IL-6 production. Finally, we suggest that upregulation of Smad3 after an ischemic insult may contribute to the increased risk for chronic kidney disease that occurs after acute renal ischemia.

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“…These findings are consistent with observations that cellular induction of ET-1 by TGF-␤1 requires Smad3 (5,41).…”

Section: 31 34 50) Our Data Demonstrate That Smad3supporting

confidence: 93%

Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury

Nath

Croatt

Warner

et al. 2011

American Journal of Physiology-Renal Physiology

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“…Here too, ET-1 may play a role. Acting via ETB receptors present on endothelial cells, ET-1 modulates various stages of neovascularization, including endothelial cell proliferation, migration, and invasion (52,53). ECE-1 knockdown is therefore a promising approach for inhibiting ET-1 release as well as for inhibiting its actions in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Small Interfering RNA Molecules Targeting Endothelin-Converting Enzyme-1 Inhibit Endothelin-1 Synthesis and the Invasive Phenotype of Ovarian Carcinoma Cells

et al. 2008

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Endothelin-1 (ET-1) has been implicated in the progression of various cancers, including ovarian carcinoma. We found that the ovarian carcinoma cell lines ES2 and OVCAR3 and tumors from different anatomic sites expressed ET-1 system members [ET receptor A and ET-converting enzyme-1 (ECE-1)]. However, only ECE-1 was significantly higher in the solid tumors compared with effusions. We therefore investigated the effect of RNA interference-induced knockdown of ECE-1, the key enzyme in ET-1 production, on these two ovarian carcinoma cell lines. Small interfering RNA (siRNA) targeting of ECE-1 markedly reduced ECE-1 mRNA and protein levels, which subsequently led to 80% to 90% inhibition of ET-1 peptide secretion by the cells. ECE-1 silencing also profoundly affected the behavior of tumor cells compared with cells treated with scrambled siRNA. Silenced cells exhibited (a) reduced ET-1-dependent p44/42 mitogen-activated protein kinase phosphorylation; (b) decreased invasiveness and matrix metalloproteinase-2 activity; (c) improved adhesion to basal lamina proteins, laminin-1, and collagen IV; and (d) increased Ecadherin, an epithelial adhesion molecule, and reduced Ncadherin expression, a mesenchymal marker. Altered cell adherence is one of the hallmarks of the transformed phenotype, often characterized by the loss of the epithelial features and the gain of a mesenchymal phenotype. ECE-1 ablation did not, however, alter viable ovarian carcinoma cell numbers. Addition of exogenous ET-1 reversed the effects cited above. Taken together, these data indicate that siRNA is an effective tool for manipulating ECE-1 expression, ET-1 biosynthesis, and invasiveness of ovarian carcinoma. ECE-1 silencing may therefore develop into a promising novel anticancer therapy. [Cancer Res 2008;68(22):9265-73]

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“…30, 35 ET-1 has been identified elevated in the serum and lung of PAH patients. 6, 36 We investigated the expression of ET-1, ETAR, ETBR, and the downstream key signal transduction markers-phospho-Akt, phospho-ERK1/2, and phospho-mTOR in the CHD patients with PAH in the current study.…”

Section: Discussionmentioning

confidence: 98%

Activation of Endothelin-1 Receptor Signaling Pathways Is Associated With Neointima Formation, Neoangiogenesis and Irreversible Pulmonary Artery Hypertension in Patients With Congenital Heart Disease

Huang

Zhang

Wang

et al. 2011

Circ J

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Background: It is unclear why some patients, who undergo complete repair or palliative surgery for congenital heart disease (CHD), still develop irreversible pulmonary artery hypertension (PAH). There is no consensus to preoperationally assess the reversible and irreversible pulmonary vasculopathy seen in PAH. Methods and Results:The peri-operative pulmonary hemodynamic data of 16 CHD patients (reversible PAH, n=6; irreversible PAH, n=10) were analyzed. The lung biopsies were also performed during surgery for defining histopathological characteristics as well as immunohistochemical expression of endothelin-1 (ET-1), endothelin-1 receptors (ETR), and its downstream signaling markers in the small pulmonary arteries and arterioles. Neointimal formation and neoangiogenesis was characterized by increased intimal layer immunoreactivity for α-SMA, Factor VIII, CD34, and VEGF. Neointimal formation was found in 90% of patients and neoangiogenesis was found in 80% of patients with irreversible PAH. Neither was present in the reversible PAH group and the control group. Expression of ET-1 and ETR in the neointimal layer of the pulmonary arterioles was upregulated in irreversible PAH, and immunoreactivity of phospho-Akt, phospho-ERK1/2, and phospho-mTOR was also increased in irreversible PAH. Conclusions:Increased expression of ET-1, ETR, and activation of signaling pathways were observed in the pulmonary arteries and arterioles of irreversible PAH patients associated with CHD. Activation of these pathways might in turn lead to neointimal formation and neoangiogenesis and thus might contribute to irreversible pulmonary vascular abnormalities. (Circ J 2011; 75: 1463 - 1471

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Signaling by ALK5 mediates TGF-β-induced ET-1 expression in endothelial cells: a role for migration and proliferation

Cited by 90 publications

References 42 publications

Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury

Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury

Small Interfering RNA Molecules Targeting Endothelin-Converting Enzyme-1 Inhibit Endothelin-1 Synthesis and the Invasive Phenotype of Ovarian Carcinoma Cells

Activation of Endothelin-1 Receptor Signaling Pathways Is Associated With Neointima Formation, Neoangiogenesis and Irreversible Pulmonary Artery Hypertension in Patients With Congenital Heart Disease

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