ALK1-Smad1/5 signaling pathway in fibrosis development: Friend or foe?

Muñoz‐Félix, José M.; González-Núñez, María; López‐Novoa, José M.

doi:10.1016/j.cytogfr.2013.08.002

Cited by 60 publications

(50 citation statements)

References 177 publications

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“…It has been already described that renal levels of phospho-Smad1/5/8 increases after UUO [50]. In the present study, we demonstrate that the levels of Smad1 phosphorylation after UUO are lower in S-ENG + than in WT mice, which suggest a role for the ALK1/Smad1 pathway in the generation of renal fibrosis in the kidney, as previously suggested [56].…”

Section: Accepted Manuscriptsupporting

confidence: 82%

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

Muñoz‐Félix

Pérez-Roque

Núñez-Gómez

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Transforming growth factor beta 1 (TGF-β1) is one of the most studied cytokines involved in renal tubulo-interstitial fibrosis, which is characterized by myofibroblast abundance and proliferation, and high buildup of extracellular matrix in the tubular interstitium leading to organ failure. Endoglin (Eng) is a 180-kDa homodimeric transmembrane protein that regulates a great number of TGF-β1 actions in different biological processes, including ECM synthesis. High levels of Eng have been observed in experimental models of renal fibrosis or in biopsies from patients with chronic kidney disease. In humans and mice, two Eng isoforms are generated by alternative splicing, L-Eng and S-Eng that differ in the length and composition of their cytoplasmic domains. We have previously described that L-Eng overexpression promotes renal fibrosis after unilateral ureteral obstruction (UUO). However, the role of S-Eng in renal fibrosis is unknown and its study would let us analyze the possible function of the cytoplasmic domain of Eng in this process. For this purpose, we have generated a mice strain that overexpresses S-Eng (S-ENG(+)) and we have performed an UUO in S-ENG(+) and their wild type (WT) control mice. Our results indicate that obstructed kidney of S-ENG(+) mice shows lower levels of tubulo-interstitial fibrosis, less inflammation and less interstitial cell proliferation than WT littermates. Moreover, S-ENG(+) mice show less activation of Smad1 and Smad2/3 pathways. Thus, S-Eng overexpression reduces UUO-induced renal fibrosis and some associated mechanisms. As L-Eng overexpression provokes renal fibrosis we conclude that Eng-mediated induction of renal fibrosis in this model is dependent on its cytoplasmic domain.

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Section: Accepted Manuscriptsupporting

confidence: 82%

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

Muñoz‐Félix

Pérez-Roque

Núñez-Gómez

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Consistent with the observed TGFβ levels, we found a significant reduction in cardiac SMAD3 level (p=0.03, Figure 2C) in male IUGR fetuses compared to controls female control and in IUGR were similar. The activin receptor-like kinase-1 (ALK1) is a type I cell-surface receptor for the TGF-β family of proteins and has been shown to play an important role in cardiovascular remodeling [47, 48]. The protein levels of cardiac ALK1 were decreased in male IUGR baboons (p=0.03), while female control and IUGR were similar.…”

Section: Resultsmentioning

confidence: 99%

Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction

Muralimanoharan

Nakayasu

et al. 2017

Journal of Molecular and Cellular Cardiology

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Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p<0.05) in male IUGR s. Expression of cardiac fibrotic markers TGFβ, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p<0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and. females (p<0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4α, and NFκB p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk.

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“…Tumor lesions from patients treated with cediranib displayed a selective down-regulation of angiopoietin 2 (ANGPT2) and the up-regulation of its receptor TIE2. This opposite gene modulation may favor the angiopoietin 1 (ANGPT1)-TIE2 interaction and, together with the down-modulation of VEGFR1 (FLT1) and VEGFR2 (KDR), drive a physiological normalization of the vasculature at tumor site [2]. This hypothesis is also supported by the findings that genes encoding for proteins expressed by endothelial precursor cells or by the tumor-associated neo-vasculature such as Folate receptor 1 (FOLH1, known also as PMSA), CXCR7 and ESM1, [3-6] were also down-modulated.…”

Section: Commentarymentioning

confidence: 99%

Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma

Castelli

Tazzari

Negri³

et al. 2013

J Transl Med

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Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma and the clinical management of patients with unresectable, metastatic disease is still challenging. ASPS expresses an array of potentially therapeutically targetable, angiogenesis-related molecules and, importantly, it has a distinctive angiogenic phenotype marked by a peculiar tumor-associated vasculature. Several studies, conducted in transgenic mouse models and in a large variety of human tumors of different histotype, clearly proved the substantial contribution of tumor-infiltrating myeloid cells, such as myeloid derived suppressor cells, monocytes and macrophages, in the formation and maintenance of abnormal blood vessels in tumors. By immunohistochemistry we thus explored the presence and the distribution of cells expressing myeloid markers in the inflammatory infiltrate of surgical treated metastatic ASPS. Indeed, we found that myeloid cells expressing CD14 and CD163 markers constitute the prominent cells in the inflammatory infiltrate of ASPS. These macrophage-like cells form a network surrounding the endothelial cells, or, interspersed in the tumor nest, they keep deep contact with tumor cells. In this commentary, we discussed our findings in relation to the recently published paper by Kummar and colleagues reporting the clinical and molecular results of a phase II clinical trial in patients with unresectable, metastatic ASPS treated with the anti-angiogenic drug cediranib, targeting the VEGFR-1,-2,-3 tyrosine kinases.

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ALK1-Smad1/5 signaling pathway in fibrosis development: Friend or foe?

Cited by 60 publications

References 177 publications

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction

Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma

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