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• W2025676889 abstract "Excessive recruitment of monocytes and progression of fibrosis are hallmarks of chronic kidney disease (CKD). Recently we reported that the expression of connexin 43 (Cx43) was upregulated in the kidney during experimental nephropathy. To investigate the role of Cx43 in the progression of CKD, we interbred RenTg mice, a genetic model of hypertension-induced CKD, with Cx43+/- mice. The renal cortex of 5-month-old RenTgCx43+/- mice showed a marked decrease of cell adhesion markers leading to reduced monocyte infiltration and interstitial renal fibrosis compared with their littermates. In addition, functional and histological parameters such as albuminuria and glomerulosclerosis were ameliorated in RenTgCx43+/- mice. Interestingly, treatment with Cx43 antisense produced remarkable improvement of renal function and structure in 1-year-old RenTg mice. Similar results were found in Cx43+/- or wild-type mice treated with Cx43 antisense after obstructive nephropathy. Furthermore, in these mice, Cx43 antisense attenuated E-cadherin downregulation and phosphorylation of the transcription factor Sp1 by the ERK pathway resulting in decreased transcription of type I collagen gene. Interestingly, Cx43-specific blocking peptide inhibited monocyte adhesion in activated endothelium and profibrotic pathways in tubular cells. Cx43 was highly increased in biopsies of patients with CKD. Thus, Cx43 may represent a new therapeutic target against the progression of CKD. Excessive recruitment of monocytes and progression of fibrosis are hallmarks of chronic kidney disease (CKD). Recently we reported that the expression of connexin 43 (Cx43) was upregulated in the kidney during experimental nephropathy. To investigate the role of Cx43 in the progression of CKD, we interbred RenTg mice, a genetic model of hypertension-induced CKD, with Cx43+/- mice. The renal cortex of 5-month-old RenTgCx43+/- mice showed a marked decrease of cell adhesion markers leading to reduced monocyte infiltration and interstitial renal fibrosis compared with their littermates. In addition, functional and histological parameters such as albuminuria and glomerulosclerosis were ameliorated in RenTgCx43+/- mice. Interestingly, treatment with Cx43 antisense produced remarkable improvement of renal function and structure in 1-year-old RenTg mice. Similar results were found in Cx43+/- or wild-type mice treated with Cx43 antisense after obstructive nephropathy. Furthermore, in these mice, Cx43 antisense attenuated E-cadherin downregulation and phosphorylation of the transcription factor Sp1 by the ERK pathway resulting in decreased transcription of type I collagen gene. Interestingly, Cx43-specific blocking peptide inhibited monocyte adhesion in activated endothelium and profibrotic pathways in tubular cells. Cx43 was highly increased in biopsies of patients with CKD. Thus, Cx43 may represent a new therapeutic target against the progression of CKD. The number of patients suffering from CKD is growing worldwide because of aging of the population, improved survival from cardiovascular diseases, and spreading of type-2 diabetes. CKD is characterized by chronic inflammation leading to abnormal accumulation of extracellular matrix components (mainly collagens type I and III) and structural alterations within all renal compartments.1.Harris R.C. Neilson E.G. Toward a unified theory of renal progression.Annu Rev Med. 2006; 57: 365-380Crossref PubMed Scopus (147) Google Scholar,2.Dussaule J.C. Chatziantoniou C. Reversal of renal disease: is it enough to inhibit the action of angiotensin II?.Cell Death Differ. 2007; 14: 1343-1349Crossref PubMed Scopus (32) Google Scholar Thus, arresting or reversing the progression of renal disease represents one of the major challenges in public health and there is an urgent need to identify new targets of therapy. Recruitment of leukocytes from the blood to the injured site is an important step in the inflammatory cascade, and gap junctions (GJs) are highly implicated in this process.3.Chanson M. Derouette J.P. Roth I. et al.Gap junctional communication in tissue inflammation and repair.Biochim Biophys Acta. 2005; 1711: 197-207Crossref PubMed Scopus (114) Google Scholar,4.Scheckenbach K.E. Crespin S. Kwak B.R. et al.Connexin channel-dependent signaling pathways in inflammation.J Vasc Res. 2011; 48: 91-103Crossref PubMed Scopus (67) Google Scholar GJ channels are formed by the multimeric assembly of connexins (Cxs), being specialized in the control of direct exchange of small metabolites between adjacent cells. To date, over 20 Cx isoforms have been characterized in mammalian cells.5.Saez J.C. Berthoud V.M. Branes M.C. et al.Plasma membrane channels formed by connexins: their regulation and functions.Physiol Rev. 2003; 83: 1359-1400Crossref PubMed Scopus (983) Google Scholar,6.Sohl G. Willecke K. Gap junctions and the connexin protein family.Cardiovasc Res. 2004; 62: 228-232Crossref PubMed Scopus (777) Google Scholar One GJ channel results from the docking of two hemichannels or connexons. Each connexon is assembled from six Cx proteins and can open under both physiological and pathological conditions. Connexons and GJ channels may be formed by different Cxs.7.Harris A.L. Emerging issues of connexin channels: biophysics fills the gap.Q Rev Biophys. 2001; 34: 325-472Crossref PubMed Google Scholar,8.Goodenough D.A. Paul D.L. Beyond the gap: functions of unpaired connexon channels.Nat Rev Mol Cell Biol. 2003; 4: 285-294Crossref PubMed Scopus (583) Google Scholar Each type of Cx-made channel has unique inherent gating properties or permeabilities to various molecules and ions. Thus, the Cx composition of GJ channels appeared to determine selectivity for different second messengers.9.Bevans C.G. Kordel M. Rhee S.K. et al.Isoform composition of connexin channels determines selectivity among second messengers and uncharged molecules.J Biol Chem. 1998; 273: 2808-2816Crossref PubMed Scopus (280) Google Scholar We have previously reported that Cxs are able to regulate monocyte adhesion in chronic vascular inflammatory diseases.10.Wong C.W. Christen T. Roth I. et al.Connexin37 protects against atherosclerosis by regulating monocyte adhesion.Nat Med. 2006; 12: 950-954Crossref PubMed Scopus (246) Google Scholar,11.Chadjichristos C.E. Matter C.M. Roth I. et al.Reduced connexin43 expression limits neointima formation after balloon distension injury in hypercholesterolemic mice.Circulation. 2006; 113: 2835-2843Crossref PubMed Scopus (89) Google Scholar We have also recently demonstrated that Cx43 expression was increased in the early stages of hypertension-induced and obstructive nephropathy in the renal cortex of the diseased mice. The Cx43 upregulation was paralleled closely by that of cell adhesion molecules, indicating that this Cx may be considered an early signal of renal inflammation during the progression of CKD.12.Toubas J. Beck S. Pageaud A.L. et al.Alteration of connexin expression is an early signal for chronic kidney disease.Am J Physiol Renal Physiol. 2011; 301: F24-F32Crossref PubMed Scopus (42) Google Scholar In the present study we investigated whether targeting Cx43 expression by genetic and pharmacogenetic manipulation could alter the progression of renal disease. First, we generated a double transgenic strain by crossbreeding RenTg mice, a genetic model of hypertension-induced CKD, with mice in which Cx43 expression was genetically reduced by half (Cx43+/-). In addition, we used Cx43+/- to perform unilateral ureteral obstruction (UUO), another model of CKD in which the initiating cause is tubulointerstitial inflammation. Finally, we inhibited the Cx43 upregulation in wild-type (WT) mice by delivering an oligodeoxynucleotide antisense (AS) in the two above-mentioned models of experimental nephropathy. Our results demonstrate for the first time that reduction of Cx43 expression limited inflammatory cell infiltration as well as renal fibrosis and markedly improved renal structure and function, indicating that this protein may represent a new therapeutic target against the progression of CKD. We have previously demonstrated that Cx43 expression is increased in RenTg mice since the early stages of the disease.12.Toubas J. Beck S. Pageaud A.L. et al.Alteration of connexin expression is an early signal for chronic kidney disease.Am J Physiol Renal Physiol. 2011; 301: F24-F32Crossref PubMed Scopus (42) Google Scholar In addition, immunofluorescence showed that Cx43 was strongly increased within injured kidneys during the progression of disease (Supplementary Figure S1 online). To obtain further insight into the implication of Cx43 in hypertension-induced CKD, we first attempted to inhibit the Cx43 upregulation in these mice. Given that the Cx43 knockout mouse dies shortly after birth,13.Reaume A.G. de Sousa P.A. Kulkarni S. et al.Cardiac malformation in neonatal mice lacking connexin43.Science. 2005; 267: 1831-1834Crossref Scopus (1126) Google Scholar we interbred RenTg with Cx43+/- to generate RenTgCx43+/- mice. As the role of Cx43 in the modulation of blood pressure is controversial,14.Liao Y. Day K.H. Damon D.N. et al.Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice.Proc Natl Acad Sci USA. 2001; 98: 9989-9994Crossref PubMed Scopus (199) Google Scholar, 15.Haefliger J.A. Krattinger N. Martin D. et al.Connexin43-dependent mechanism modulates renin secretion and hypertension.J Clin Invest. 2006; 116: 405-413Crossref PubMed Scopus (90) Google Scholar, 16.Figueroa X.F. Isakson B.E. Duling B.R. Vascular gap junctions in hypertension.Hypertension. 2006; 48: 804-811Crossref PubMed Scopus (63) Google Scholar we first compared arterial pressure between RenTgCx43+/-, RenTgCx43+/+, and WT mice aged 5 months (mo). Systolic blood pressure was significantly increased in hypertensive mice compared with WT controls (Figure 1a). However, decreasing expression of Cx43 did not modulate systolic blood pressure (150±6.5mmHg in RenTgCx43+/+ and 152±6.1mmHg in RenTgCx43+/-). Therefore, phenotypic observations due to the genetic deletion of Cx43 are independent from blood pressure. In addition, we confirmed the overexpression of Cx43 messenger RNA (mRNA) in RenTgCx43+/+ mice compared with WT healthy animals. This upregulation was blunted in 5-mo-old RenTgCx43+/- mice (Figure 1b). Next, we checked whether decreased expression of Cx43 could affect the renal structure. Masson’s trichrome staining showed that 5-mo-old RenTgCx43+/+ mice presented established lesions typical of hypertension-induced CKD, such as perivascular and periglomerular inflammation, glomerular ischemia, glomerulosclerosis, and tubular dilation, compared with WT healthy animals (Figure 1c). In RenTgCx43+/- mice the renal structure was preserved, as glomerulosclerosis and tubular dilation were significantly decreased (Figure 1d and e, respectively) and consequently microalbuminuria was highly reduced (Figure 1f). Thus, decreased expression of Cx43 was associated with improved renal structure and function during the progression of hypertension-induced CKD. Download .jpg (.18 MB) Help with files Supplementary Figure S1 Next, we investigated at the same time point the relation between decreased Cx43 expression and inflammation during the progression of the disease. Quantitative PCR showed that mRNA expression for C-C chemokine receptor type 2 and vascular adhesion molecule-1 (VCAM-1) was highly upregulated in RenTgCx43+/+ mice compared with WT healthy animals (Figure 2a and b, respectively). In RenTgCx43+/- this increase was significantly restricted. In addition, F4-80 immunostaining showed a pronounced inflammatory cell infiltration in cortical slices of RenTgCx43+/+ mice (Figure 2c). In contrast, monocyte recruitment was highly reduced in RenTgCx43+/- animals (Figure 2d). To explore whether Cx43 could control the leukocyte recruitment, we compared adhesion of the RenTgCx43+/+ and RenTgCx43+/- monocytes collected after peritoneal lavage with an activated mouse endothelial cell monolayer. As shown in Figure 2e, the number of adherent Cx43-deficient monocytes was considerably reduced. Thus, reduced Cx43 expression leads to restricted interstitial inflammation during the progression of hypertension-induced CKD. Given that Cx43 downregulation limited monocyte infiltration, we hypothesized that this protein may influence the development of renal fibrosis. As expected, quantitative PCR showed a marked upregulation of the mRNAs of transforming growth factor-β1 (TGF-β1) and type I collagen (Col1) in RenTgCx43+/+ mice. This upregulation was blunted in the RenTgCx43+/- animals (Figure 2f and g, respectively). In accordance, Sirius Red coloration demonstrated a decreased interstitial collagen deposition in the cortex of RenTgCx43+/- mice (Figure 2h). We can thus conclude that Cx43 contributes to interstitial renal fibrosis in addition to monocyte infiltration during the progression of hypertension-induced CKD. To investigate whether Cx43 could be a potential therapeutic target against the progression of CKD, we blocked its overexpression by using Cx43AS, known to specifically decrease Cx43 expression.17.Chadjichristos C.E. Morel S. Derouette J.P. et al.Targeting connexin 43 prevents platelet-derived growth factor-BB-induced phenotypic change in porcine coronary artery smooth muscle cells.Circ Res. 2008; 102: 653-660Crossref PubMed Scopus (56) Google Scholar, 18.Qiu C. Coutinho P. Frank S. et al.Targeting connexin43 expression accelerates the rate of wound repair.Curr Biol. 2003; 13: 1697-1703Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 19.Cronin M. Anderson P.N. Cook J.E. et al.Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury.Mol Cell Neurosci. 2008; 39: 152-160Crossref PubMed Scopus (162) Google Scholar, 20.Nakano Y. Oyamada M. Dai P. et al.Connexin43 knockdown accelerates wound healing but inhibits mesenchymal transition after corneal endothelial injury in vivo.Invest Ophthalmol Vis Sci. 2008; 49: 93-104Crossref PubMed Scopus (93) Google Scholar This AS was administered to 11-mo-old RenTg mice, suffering thus from advanced hypertension-induced CKD, for 1 mo via minipump infusion. Scrambled (SCR) sequence was used as control. As illustrated in Figure 3a, Masson’s trichrome showed that the renal structure of 1-year-old RenTg mice treated with SCR was considerably damaged. In contrast, RenTg mice treated with Cx43AS showed a substantial improvement in renal structure as glomerulosclerosis and tubular dilation were significantly reduced (Figure 3b and c, respectively). Consequently, CKD progression was hindered as renal function was highly ameliorated (Figure 3d). In addition, decreased expression of Cx43 (Figure 3e) led to a lesser upregulation of VCAM-1 at both mRNA (Figure 3f) and protein levels (Supplementary Figure S2 online), and consequently limited monocyte infiltration (Figure 3g). Furthermore, upregulation of col1 and TGF-β1 mRNA levels was blunted in RenTg animals following AS infusion (Figure 3h and i, respectively) and consequently interstitial fibrosis was also reduced (Figure 3j). These data suggest that Cx43 may be used as a therapeutic target against the progression of hypertension-induced CKD. Download .jpg (.05 MB) Help with files Supplementary Figure S2 Increased expression of Cx43 was also observed during the progression of obstructive nephropathy within injured kidneys in WT mice (Supplementary Figure S3 online). To investigate whether the potential protective effect of Cx43 blockade is not model dependent, Cx43+/- and their littermates underwent UUO and were euthanized after 7 and 15 days (d). Cx43 mRNA upregulation was confirmed 7d after UUO (Figure 4a), and as expected an increased expression of the mRNA of VCAM-1 (b), P-selectin (c), and chemokine receptor type 2 (d) was also observed. In contrast, at the same time point this upregulation was significantly reduced in Cx43+/- mice. As monocytes have a major role in the inflammatory process in this model of renal nephropathy,21.Guerrot D. Kerroch M. Placier S. et al.Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy.Am J Pathol. 2001; 179: 83-91Abstract Full Text Full Text PDF Scopus (90) Google Scholar we next performed F4-80 immunostaining. An important macrophage infiltration was detected in the interstitium of the obstructed kidneys 7d after UUO, whereas in Cx43+/- mice the infiltrate was significantly reduced (Figure 4e). Next, we studied the impact of the Cx43 deletion on the progression of interstitial renal fibrosis 15d after UUO. We observed that Col1 and Col3 mRNA levels increased significantly after UUO compared with the levels in the contralateral nonobstructive kidneys (Figure 4g and h, respectively). However, upregulation of mRNA expression of both collagens was blunted in Cx43+/- and the accumulation of interstitial collagen formation was also reduced (Figure 4i). Furthermore, immunostaining for fibroblast-specific protein-1, a well-established fibrotic marker, showed limited fibroblast-specific protein-1-positive cells after UUO in Cx43+/- mice (Supplementary Figure S4 online). In conclusion, similar to hypertension-induced nephropathy, decreased expression of Cx43 limited the inflammatory reaction and decreased excessive extracellular matrix accumulation, leading to improved renal structure. Download .jpg (.17 MB) Help with files Supplementary Figure S3 Download .jpg (.1 MB) Help with files Supplementary Figure S4 To confirm the protective effect of the Cx43-decreased expression after UUO, we injected a Cx43-ODN AS or a SCR sequence locally in the dilated ureter 24h after obstruction. Mice were killed 7d after UUO. To quantify the extent of Cx43 knockdown after the AS administration, we assessed Cx43 expression by quantitative PCR. As shown in Figure 5a, the upregulation of the Cx43 mRNA expression was attenuated after the AS injection. In addition, we observed a marked decrease in the VCAM-1 mRNA and protein expressions in the obstructed kidneys that received Cx43AS compared with those that received SCR after UUO (Figure 5b and c, respectively). Interestingly, western blotting for E-cadherin, a marker of renal tubular epithelial phenotype, showed that its expression was partially restored after AS treatment, indicating an improvement in the renal structure. In accordance, macrophage infiltration was clearly decreased in Cx43AS-treated kidneys (Figure 5f and g). As previously observed, limitation of cell infiltration at the injured site resulted in restricted interstitial fibrosis. Given that GJs are implicated in pathways regulating the transcription of the target genes, we speculated that signaling passing through the Cx43 channels could affect the expression of the col1 gene after UUO. We focused directly on the extracellular signal-regulated kinase (ERK) signaling pathway that has been shown to regulate the phosphorylation and transcriptional activity of Sp1, known to be a powerful activator of the transcription of the col1 gene.22.Milanini-Mongiat J. Pouysségur J. Pagès G. Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription.J Biol Chem. 2002; 277: 20631-20639Crossref PubMed Scopus (258) Google Scholar,23.Kypriotou M. Beauchef G. Chadjichristos C. et al.Human collagen Krox up-regulates type I collagen expression in normal and scleroderma fibroblasts through interaction with Sp1 and Sp3 transcription factors.J Biol Chem. 2007; 282: 32000-32014Crossref PubMed Scopus (43) Google Scholar Mice that received SCR sequence after UUO had a pronounced activation of the ERK activity as the phosphorylation of ERK was highly increased (Figure 6a and b). The phosphorylated form of the Sp1 transcription factor was also markedly increased (Figure 6a and c). At the same time point, the expression of col1 mRNA was increased by almost 50-fold. In contrast, local treatment with Cx43AS reduced the phosphorylation of ERK by half and abolished the phosphorylation of Sp1, leading to a significant reduction in col1 mRNA expression (Figure 6d). Furthermore, Cx43AS significantly reduced mRNA expression of TGF-β1, one of the most important profibrotic cytokines in renal damage (Figure 6e). These data demonstrate that decreasing the Cx43 expression limited the inflammatory process and restricted interstitial renal fibrosis and thus resulted in renal structure preservation.Figure 6Connexin 43 (Cx43)-ODN antisense (AS) decreased fibrotic pathways in obstructed kidneys of wild-type (WT) mice. Representative western blotting experiments for P-extracellular signal-regulated kinase (ERK), ERK, Sp1, and GAPDH were performed by using the renal cortex of nonobstructed contralateral controls and obstructed kidneys after administration of Cx43AS or scrambled (SCR) sequence (a). Graphs show quantification of western blots expressed as the ratio of P-ERK/ERK (b) and Sp1 (c) vs. GAPDH for each sample. Quantitative PCR (qPCR) in the renal cortex showed that delivery of Cx43AS in the dilated ureter decreased the Col1 (d) and transforming growth factor-β1 (TGF-β1) (e) upregulation 7d after unilateral ureteral obstruction (UUO; n=6, *P<0.05, **P<0.01, ***P<0.001). GAPDH, glyceraldehyde 3-phosphate dehydrogenase.View Large Image Figure ViewerDownload (PPT) In the above-mentioned models of CKD, Cx43 seemed to participate in two essential processes during the progression of the disease: monocyte recruitment and tissue fibrosis. To assess the functional importance of Cx43, we used Gap26 peptide, a Cx43-specific GJ blocker that inhibits the docking of the Cx43 hemichannels and consequently the Cx43-mediated GJ intercellular communication (GJIC).17.Chadjichristos C.E. Morel S. Derouette J.P. et al.Targeting connexin 43 prevents platelet-derived growth factor-BB-induced phenotypic change in porcine coronary artery smooth muscle cells.Circ Res. 2008; 102: 653-660Crossref PubMed Scopus (56) Google Scholar As shown in Supplementary Figure S5A online, the number of monocytes that adhere to an activated mouse endothelial cell monolayer previously incubated with Gap26 was significantly reduced. In addition, freshly extracted monocytes incubated with Gap26 showed considerably less adhesion to the activated bEnd3 monolayer. These data showed that Cx43 expression may have a proadhesive role mainly in monocytes and to a lesser extent in activated endothelial cells. Download .jpg (.13 MB) Help with files Supplementary Figure S5 To study the functional importance of Cx43 in profibrotic pathways we first incubated mouse tubular cells (mCCDs) with TGF-β1. This stimulation led to de novo expression of Cx43 mainly between the neighboring cells (Supplementary Figure S5B online). Furthermore, incubation of tubular cells with Gap26 inhibited the TGF-β1-induced ERK pathway (Supplementary Figure S5C and D online), the phosphorylation of the transcription factor Sp1, and the upregulation of col1 (Supplementary Figure S5E and F online, respectively). Thus, Cx43 may participate in the profibrotic effects of TGF-β1 through the exchange of second messengers passing through the Cx43 channels. Impairment of GJIC has been reported to have a large impact on various diseases.4.Scheckenbach K.E. Crespin S. Kwak B.R. et al.Connexin channel-dependent signaling pathways in inflammation.J Vasc Res. 2011; 48: 91-103Crossref PubMed Scopus (67) Google Scholar In this study we demonstrated for the first time that Cx43 upregulation contributes to structural damages within the renal cortex during the progression of renal disease, and inhibiting its expression improved tissue structure and function. To investigate whether Cx43 could be a key mediator of renal disease, we took advantage of two different mouse models of CKD. The first, the RenTg model, has been recently described as a powerful tool for studying CKD as it presents all physiopathological characteristics of a slowly progressive hypertension-induced renal disease.24.Huby A.C. Kavvadas P. Alfieri C. et al.The RenTg mice: a powerful tool to study renin-dependent chronic kidney disease.PLoS One. 2012; 7: e52362Crossref PubMed Scopus (14) Google Scholar The second, the UUO, is a well-established model of tubulointerstitial renal disease leading to renal fibrosis.25.Chevalier R.L. Forbes M.S. Thornhill B.A. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy.Kidney Int. 2009; 75: 1145-1152Abstract Full Text Full Text PDF PubMed Scopus (710) Google Scholar Although these two experimental models target distinct renal compartments, they are linked by their ability to promote development of chronic inflammation and fibrosis leading to severe damages to the renal structure. In both models we showed that Cx43 expression was increased during the progression of renal disease (Supplementary Figure S1 and S3 online) and that decreased Cx43 expression was beneficial in chronic inflammation. This process requires cross-talks between leukocytes and the injured tissue and a high level of coordination in which GJs are involved. It has been reported that in various stages of inflammatory diseases Cx43 expression and distribution can markedly change, thus modulating the progression of the injury.3.Chanson M. Derouette J.P. Roth I. et al.Gap junctional communication in tissue inflammation and repair.Biochim Biophys Acta. 2005; 1711: 197-207Crossref PubMed Scopus (114) Google Scholar,26.Sarieddine M.Z. Scheckenbach K.L. Foglia B. et al.Connexin43 modulates neutrophil recruitment to the lung.J Cell Mol Med. 2009; 13: 4560-4570Crossref PubMed Scopus (90) Google Scholar,27.Ey B. Eyking A. Gerken G. et al.TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury.J Biol Chem. 2009; 284: 22332-22343Crossref PubMed Scopus (93) Google Scholar Indeed, in chronic models of inflammation in mice, such as atherosclerosis, an upregulation of Cx43 by the dysfunctional vascular endothelium was detected in the shoulder of the lesions, as well as in intimal smooth muscle cells at the early stages of the disease.28.Kwak B.R. Mulhaupt F. Veillard N. et al.Altered pattern of vascular connexin expression in atherosclerotic plaques.Arterioscler Thromb Vasc Biol. 2002; 22: 225-230Crossref PubMed Scopus (204) Google Scholar Similar temporal expression patterns of Cx43 were also observed in rodents, in the muscular microcirculation following inflammatory stimulation, in obstructed kidneys, and in myocardial endothelial–mesenchymal transition.29.Véliz L.P. González F.G. Duling B.R. et al.Functional role of gap junctions in cytokine-induced leukocyte adhesion to endothelium in vivo.Am J Physiol Heart Circ Physiol. 2008; 295: 1056-1066Crossref PubMed Scopus (46) Google Scholar, 30.Sommer M. Eismann U. Deuther-Conrad W. et al.Time course of cytokine mRNA expression in kidneys of rats with unilateral ureteral obstruction.Nephron. 2000; 84: 49-57Crossref PubMed Scopus (18) Google Scholar, 31.Asazuma-Nakamura Y. Dai P. Harada Y. et al.Cx43 contributes to TGF-beta signaling to regulate differentiation of cardiac fibroblasts into myofibroblasts.Exp Cell Res. 2009; 315: 1190-1199Crossref PubMed Scopus (53) Google Scholar In addition, it has been reported that Cx43 expression was enhanced in damaged tubules and interstitial cells in human kidneys and in rat podocytes in puromycin aminonucleoside nephrosis.32.Hillis G.S. Duthie L.A. Brown P.A. et al.Upregulation and co-localization of connexin43 and cellular adhesion molecules in inflammatory renal disease.J Pathol. 1997; 182: 373-379Crossref PubMed Scopus (47) Google Scholar,33.Yaoita E. Yao J. Yoshida Y. et al.Up-regulation of connexin43 in glomerular podocytes in response to injury.Am J Pathol. 2002; 161: 1597-1606Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar The Cx43+/- mouse has been used in several diseases to investigate the link between Cx43 and inflammation. Thus, in accordance with our study, in LDLR (low-density lipoprotein receptor)–deficient mice with reduced Cx43 levels, atherogenesis was markedly inhibited and the composition of the atherosclerotic plaques exhibited reduced amount of leukocytes.34.Kwak B.R. Veillard N. Pelli G. et al.Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice.Circulation. 2003; 107: 1033-1039Crossref PubMed Scopus (148) Google Scholar Additional studies in the same model showed limited local monocyte infiltration leadin" @default.
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• W2025676889 title "Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice" @default.
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