Galectin-3 preserves renal tubules and modulates extracellular matrix remodeling in progressive fibrosis

Renal tubular cell apoptosis is a critical detrimental event that leads to chronic kidney injury in association with renal fibrosis. The present study was designed to investigate the role of galectin-3 (Gal-3), an important regulator of multiple apoptotic pathways, in chronic kidney disease induced by unilateral ureteral obstruction (UUO). After UUO, Gal-3 expression significantly increased compared with basal levels reaching a peak increase of 95-fold by day 7. Upregulated Gal-3 is predominantly tubular at early time points after UUO but shifts to interstitial cells as the injury progresses. On day 14, there was a significant increase in TdT-mediated dUTP nick end labeling-positive cells (129%) and cytochrome c release (29%), and a decrease in BrdU-positive cells (62%) in Gal-3-deficient compared with wild-type mice. The degree of renal damage was more extensive in Gal-3-deficient mice at days 14 and 21, 35 and 21% increase in total collagen, respectively. Despite more severe fibrosis, myofibroblasts were significantly decreased by 58% on day 14 in the Gal-3-deficient compared with wild-type mice. There was also a corresponding 80% decrease in extracellular matrix synthesis in Gal-3-deficient compared with wild-type mice. Endo180 is a recently recognized receptor for intracellular collagen degradation that is expressed by interstitial cells during renal fibrogenesis. Endo180 expression was significantly decreased by greater than 50% in Gal-3-deficient compared with wild-type mice. Taken together, these results suggested that Gal-3 not only protects renal tubules from chronic injury by limiting apoptosis but that it may lead to enhanced matrix remodeling and fibrosis attenuation.

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Hypoxia-mediated regulation of the secretory properties of mitral valve interstitial cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00720.2016 ◽

2017 ◽

Vol 313 (1) ◽

pp. H14-H23 ◽

Cited By ~ 9

Author(s):

Kareem Salhiyyah ◽

Padmini Sarathchandra ◽

Najma Latif ◽

Magdi H. Yacoub ◽

Adrian H. Chester

Keyword(s):

Extracellular Matrix ◽

Mitral Valve ◽

Heart Valve ◽

Potential Role ◽

Complex Function ◽

Interstitial Cells ◽

Matrix Remodeling ◽

Mechanical Stimuli ◽

Valve Interstitial Cells

The sophisticated function of the mitral valve depends to a large extent on its extracellular matrix (ECM) and specific cellular components. These are tightly regulated by a repertoire of mechanical stimuli and biological pathways. One potentially important stimulus is hypoxia. The purpose of this investigation is to determine the effect of hypoxia on the regulation of mitral valve interstitial cells (MVICs) with respect to the synthesis and secretion of extracellular matrix proteins. Hypoxia resulted in reduced production of total collagen and sulfated glycosaminoglycans (sGAG) in cultured porcine MVICs. Increased gene expression of matrix metalloproteinases-1 and -9 and their tissue inhibitors 1 and 2 was also observed after incubation under hypoxic conditions for up to 24 h. Hypoxia had no effect on MVIC viability, morphology, or phenotype. MVICs expressed hypoxia-inducible factor (HIF)-1α under hypoxia. Stimulating HIF-1α chemically caused a reduction in the amount of sGAG produced, similar to the effect observed under hypoxia. Human rheumatic valves had greater expression of HIF-1α compared with normal or myxomatous degenerated valves. In conclusion, hypoxia affects the production of certain ECM proteins and expression of matrix remodeling enzymes by MVICs. The effects of hypoxia appear to correlate with the induction of HIF-1α. This study highlights a potential role of hypoxia and HIF-1α in regulating the mitral valve, which could be important in health and disease. NEW & NOTEWORTHY This study demonstrates that hypoxia regulates extracellular matrix secretion and the remodeling potential of heart valve interstitial cells. Expression of hypoxia-induced factor-1α plays a role in these effects. These data highlight the potential role of hypoxia as a physiological mediator of the complex function of heart valve cells.

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Adamts5 −/− Mice Exhibit Altered Aggrecan Proteolytic Profiles That Correlate With Ascending Aortic Anomalies

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.313077 ◽

2019 ◽

Vol 39 (10) ◽

pp. 2067-2081 ◽

Cited By ~ 9

Author(s):

Loren E. Dupuis ◽

E. Lockett Nelson ◽

Brittany Hozik ◽

Sarah C. Porto ◽

Alexandra Rogers-DeCotes ◽

...

Keyword(s):

Amino Acids ◽

Extracellular Matrix ◽

Aortic Wall ◽

Cell Loss ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Wild Type ◽

Aortic Valves ◽

Bicuspid Aortic Valves ◽

High Penetrance

Objective: Investigate the requirement of Aggrecan (Acan) cleavage during aortic wall development in a murine model with ADAMTS (a disintegrin-like and metalloprotease domain with thrombospondin-type motifs) 5 deficiency and bicuspid aortic valves. Approach: Mice with altered extracellular matrix remodeling of proteoglycans will be examined for anomalies in ascending aortic wall development. Neo-epitope antibodies that recognize ADAMTS cleaved Acan fragments will be used to investigate the mechanistic requirement of Acan turnover, in aortic wall development. Results: Adamts5 −/− ;Smad2 +/− mice exhibited a high penetrance of aortic anomalies (n=17/17); Adamts5 −/− ;Smad2 +/− mice with bicuspid aortic valves (7/17) showed a higher number of anomalies than Adamts5 −/− ;Smad2 +/− mice with tricuspid aortic valves. Single mutant Adamts5 −/− mice also displayed a high penetrance of aortic anomalies (n=19/19) compared with wild type (n=1/11). Aortic anomalies correlated with Acan accumulation that was apparent at the onset of elastogenesis in Adamts5 −/− mice. Neo-epitope antibodies that recognize the initial amino acids in the Acan cleaved fragments neo-FREEE, neo-GLGS, and neo-SSELE were increased in the Adamts5 −/− aortas compared with WT. Conversely, neo-TEGE, which recognizes highly digested Acan core fragments, was reduced in Adamts5 −/− mice. However, mice containing a mutation in the TEGE 373 ↓ 374 ALGSV site, rendering it noncleavable, had low penetrance of aortic anomalies (n=2/4). Acan neo-DIPEN and neo-FFGVG fragments were observed in the aortic adventitia; Acan neo-FFGVG was increased abnormally in the medial layer and overlapped with smooth muscle cell loss in Adamts5 −/− aortas. Conclusions: Disruption of ADAMTS5 Acan cleavage during development correlates with ascending aortic anomalies. These data indicate that the mechanism of ADAMTS5 Acan cleavage may be critical for normal aortic wall development.

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Post-stroke Delivery of Valproic Acid Promotes Functional Recovery and Differentially Modifies Responses of Peri-Infarct Microglia

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.639145 ◽

2021 ◽

Vol 14 ◽

Author(s):

Tung-Tai Kuo ◽

Vicki Wang ◽

Jui-Sheng Wu ◽

Yuan-Hao Chen ◽

Kuan-Yin Tseng

Keyword(s):

Extracellular Matrix ◽

Valproic Acid ◽

Functional Recovery ◽

Morphological Changes ◽

Infarct Volume ◽

Morphological Characteristics ◽

Matrix Remodeling ◽

Post Stroke ◽

Circularity Index ◽

Galectin 3

The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery. Next, we investigated the number and morphological characteristic of peri-infarct microglia at different time points and elucidated the mechanism of microglial response by VPA treatment. Male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (dMCAo) for 90 min, followed by reperfusion. Some received a single injection of VPA (200 mg/kg) 90 min after the induction of ischemia, while vehicle-treated animals underwent the same procedure with physiological saline. Infarction volume was calculated at 48 h after reperfusion, and neurological symptoms were evaluated. VPA didn’t significantly reduce infarct volume but did ameliorate neurological deficit at least partially compared with vehicle. Meanwhile, VPA reduced dMCAo-induced elevation of IL-6 at 24 h post-stroke and significantly decreased the number of CD11b-positive microglia within peri-infarct cortex at 7 days. Morphological analysis revealed that VPA therapy leads to higher fractal dimensions, smaller soma size and lower circularity index of CD11b-positive cells within peri-infarct cortex at both 2 and 7 days, suggesting that VPA has core effects on microglial morphology. The modulation of microglia morphology caused by VPA might involve HDAC inhibition-mediated suppression of galectin-3 production. Furthermore, qPCR analysis of CD11b-positive cells at 3 days post-stroke suggested that VPA could partially enhance M2 subset polarization of microglia in peri-infarct cortex. Analysis of VPA-induced changes to gene expressions at 3 days post-stroke implies that these alternations of the biomarkers and microglial responses are implicated in the upregulation of wound healing, collagen trimmer, and extracellular matrix genes within peri-infarct cortex. Our results are the first to show that a low dose of VPA promotes short-term functional recovery but does not alter infarct volume. The decreases in the expression of both IL-6 and galectin-3 might influence the morphological characteristics and transcriptional profiles of microglia and extracellular matrix remodeling, which could contribute to the improved recovery.

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Abstract 135: Thoracic Aortic Wall Tension Regulates microRNA-133a Abundance

Circulation Research ◽

10.1161/res.119.suppl_1.135 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Adam W Akerman ◽

Elizabeth K Nadeau ◽

Robert E Stroud ◽

Rupak Mukherjee ◽

John S Ikonomidis ◽

...

Keyword(s):

Extracellular Matrix ◽

Aortic Wall ◽

Ex Vivo ◽

Cyclic Stretch ◽

Aortic Tissue ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Wall Tension ◽

Wild Type

Background: MicroRNA-133a (miR133a) is a small non-coding RNA, which represses the translation of multiple mRNAs. This laboratory has reported an inverse relationship between aortic diameter and miR133a abundance in aortic tissue from patients with thoracic aortic aneurysm (TAA); as diameter increased, the abundance of miR133a decreased. Given that wall tension at a given pressure increases with increasing vessel diameter (Law of LaPlace), this study tested the hypothesis that elevated aortic wall tension results in a loss of miR-133a. Methods/Results: TAA was induced in wild type mice using an established murine model (0.5M CaCl 2 application, 15 min). MiR133a abundance (QPCR) was reduced in TAA tissue (3-wk TAA, 42.1±8.6% p<0.05 vs mice without TAA (100%)). In two in vivo models of elevated wall tension ( simulated hypertension ): 1) ANGII (angiotensin II infusion; 1.44mg/kg/day), and 2) BPH2 (spontaneously hypertensive mice, The Jackson Laboratory, Stock #003005), miR133a levels were decreased compared to normotensive controls (ANGII: 53.0±4.3%; BPH2: 51.7±7.0%; p<0.05 vs normotensive control (100%)). Aortic rings from wild type mice were hung on parallel wires in an ex vivo tissue myograph at 0.7 g, then ANGII (100nM) was added to the tissue baths, which generated increased tension (1.21±0.15g) and resulted in reduced tissue miR133a abundance (46.0±12%; p<0.05 vs no AngII,). Furthermore, increased tension alone (1.5g, 3 hr) resulted in decreased tissue miR133a abundance (39.0±7.0%; p<0.05 vs 0.7 g tension). Isolated primary aortic cell lines (fibroblasts (FB) and smooth muscle cells (SMC)) were exposed to biaxial cyclic stretch for 3 hr. FB miR133a was reduced (62.8±8.3%; p<0.05 vs unstretched control (100%)), while SMC miR133a abundance remained unchanged. Conclusion: The significance of these unique findings is 2-fold: First, tension alone was sufficient to decrease miR133a abundance in aortic tissue. Second, increased tension reduced miR133a abundance in FB, a cell type that is responsible for extracellular matrix remodeling. These findings suggest changes in wall tension alone ( hypertension ) may be associated with pathological extracellular matrix remodeling, in part, through the loss of miR133a in fibroblasts.

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Faculty Opinions recommendation of Sweet, yet underappreciated: Proteoglycans and extracellular matrix remodeling in heart disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732498270.793541733 ◽

2018 ◽

Author(s):

Nikos Karamanos

Keyword(s):

Extracellular Matrix ◽

Heart Disease ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling

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The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽

10.3390/cells10051046 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1046

Author(s):

Jorge Martinez ◽

Patricio C. Smith

Keyword(s):

Extracellular Matrix ◽

Type I Collagen ◽

Cell Metabolism ◽

Breast Tumors ◽

Extracellular Matrix Remodeling ◽

Type I ◽

Matrix Remodeling ◽

Desmoplastic Reaction ◽

The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

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Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00563-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Wei Dai ◽

Shenglan Liu ◽

Shubo Wang ◽

Li Zhao ◽

Xiao Yang ◽

...

Keyword(s):

Extracellular Matrix ◽

Cancer Cells ◽

Uveal Melanoma ◽

Specific Inhibitor ◽

Type I ◽

Matrix Remodeling ◽

Metastatic Colonization ◽

Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

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