Effects of Anti-α1 Integrin Subunit Antibody on Anti-Thy-1 Glomerulonephritis

Kubo, Shoji; Urushihara, Maki; Kondo, Shuji; Hayashi, Toshihiko; Yamano, Hiroko; Löster, Klemens; Vossmeyer, Dörte; Reutter, Werner; Kuroda, Yasuhiro

doi:10.1097/01.lab.0000027835.77351.bf

Cited by 20 publications

(19 citation statements)

References 25 publications

(45 reference statements)

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“…In many fibrotic renal diseases, coordinate induction of the synthesis of matrix proteins and integrins (␣1 or ␣5) was observed (2). An antibody to ␣1 decreased mesangial matrix accumulation in a rat model of glomerulonephritis (25). Overexpression of ␣1␤1 in mesangial cells led to reorganization of the extracellular matrix (26).…”

Section: Discussionmentioning

confidence: 99%

Glomerular and Renal Vascular Structural Changes in α8 Integrin-Deficient Mice

Haas¹,

Amann²,

Schittny³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the ␣8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. ␣8-deficient (␣8Ϫ/Ϫ) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of ␣8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of ␣8Ϫ/Ϫ mice would be completely normal. Therefore, the renal phenotype of adult ␣8Ϫ/Ϫ mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. ␣8Ϫ/Ϫ mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and ␣8Ϫ/Ϫ mice. Quantitative morphologic analyses revealed that the glomeruli of ␣8Ϫ/Ϫ mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the ␣8 ligand fibronectin) was expanded in ␣8Ϫ/Ϫ mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of ␣8Ϫ/Ϫ mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor ␣2 integrin in ␣8Ϫ/Ϫ mice. The glomerular capillary length density was significantly greater in ␣8Ϫ/Ϫ mice than in wild-type mice. Cortical arterial vessel walls were not altered in ␣8Ϫ/Ϫ mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of ␣8, glomerular and renal vascular alterations in ␣8Ϫ/Ϫ mice were relatively mild. Only aged ␣8Ϫ/Ϫ mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of ␣8 can be largely compensated for, at least in younger ␣8Ϫ/Ϫ mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor ␣2 contribute to maintaining the glomerular structure in ␣8Ϫ/Ϫ mice. The compensatory mechanisms involved will be the subject of future research.Integrins are heterodimeric transmembrane glycoproteins, each consisting of two noncovalently linked chains, the ␣ and ␤ subunits. Eighteen ␣ and eight ␤ chains have been identified; they combine to form 24 integrin receptor types (1). Cellmatrix interactions mediated mainly by integrins of the ␤1 family play important roles in embryogenesis and maintenance of the normal structure and function of organs, including the kidney (1). Furthermore, many human and experimental renal diseases are associated with altered expression of integrins (2), pointing to an important role for integrins in the development and/or progress...

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Section: Discussionmentioning

confidence: 99%

Glomerular and Renal Vascular Structural Changes in α8 Integrin-Deficient Mice

Haas¹,

Amann²,

Schittny³

et al. 2003

Journal of the American Society of Nephrology

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“…The differences were evaluated with the Stat Mate III software package (ATMS Co., Ltd., Tokyo, Japan). For urinary protein excretion, blood parameters, and BP, statistical significance was evaluated using a t test (8,33). The data for histology and immunohistochemistry were analyzed using the nonparametric Kruskal-Wallis test for multiple comparisons (8).…”

Section: Statistical Analysesmentioning

confidence: 99%

“…To evaluate the level of glomerular staining with each antibody, we performed semiquantitative analysis as follows: 0 ϭ diffuse, very weak, or absent mesangial staining; 1ϩ ϭ 1 to 25% of focally increased mesangial staining; 2ϩ ϭ 25 to 50% of glomerular tuft demonstrating strong mesangial staining; 3ϩ ϭ 50 to 75% of glomerular tuft demonstrating strong mesangial staining; and 4ϩ ϭ Ͼ75% of glomerular tuft stained strongly. For each kidney section, 30 glomeruli were selected at random and evaluated by the same blinded pathologist; the mean value per section was calculated (33).…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Addition of the Antioxidant Probucol to Angiotensin II Type I Receptor Antagonist Arrests Progressive Mesangioproliferative Glomerulonephritis in the Rat

Kondo¹,

Shimizu²,

Urushihara³

et al. 2006

Journal of the American Society of Nephrology

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Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-␤1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.

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“…TGF-β induces the expression of the collagen-binding integrins α1β1 and α2β1, which mediate collagen remodeling and myofibroblast contraction (Margadant and Sonnenberg 2010). Earlier studies using cardiac fibroblasts (Carver et al 1995), smooth muscle cells (Gotwals et al 1996), stellate cells (Racine-Samson et al 1997), and mesangial cells (Kagami et al 2002) showed that blocking α1 integrin prevents collagen gel contraction. This is somehow controversial considering that α1β1 integrin does not bind with high affinity to fibrillar type I collagen and binds preferentially to the monomeric form (Jokinen et al 2004).…”

Section: Collagen Fiber Alignmentmentioning

confidence: 96%

Contribution of collagen adhesion receptors to tissue fibrosis

Coelho

McCulloch

2016

Cell Tissue Res

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Fibrosis is the result of a wound-healing response that fails to restore normal tissue structure function. One of the critical hallmarks of fibrosis is disrupted collagen remodeling. In tissue homeostasis, the production, deposition and organization of collagen is balanced by the degradation and remodeling of collagen within the existing matrix. After injury or chronic infection, tissues initiate a wound-healing response that is intended to create a new ECM for restoring tissue structure and function. If the wound-healing response is dysregulated or if the tissue injury or infection is severe or long-lasting, collagen deposition exceeds collagen degradation and the tissue repair process leads to fibrosis. The fibrotic repair response is extraordinarily complex and involves a wide spectrum of cells, signaling pathways and regulatory systems, some of which can be readily disrupted and thereby contribute to fibrotic lesions. The dysregulated collagen remodeling is a common end-point of all fibrotic disorders, and one of the rate-limiting steps of collagen remodeling is the binding of cells to collagen fibrils by specific cell adhesion receptors. In this review, we describe how the expression and function of collagen adhesion receptors contribute to collagen processing events that contribute to tissue fibrosis. Graphical abstract Balance between collagen remodeling in health and disease.

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Effects of Anti-α1 Integrin Subunit Antibody on Anti-Thy-1 Glomerulonephritis

Cited by 20 publications

References 25 publications

Glomerular and Renal Vascular Structural Changes in α8 Integrin-Deficient Mice

Glomerular and Renal Vascular Structural Changes in α8 Integrin-Deficient Mice

Addition of the Antioxidant Probucol to Angiotensin II Type I Receptor Antagonist Arrests Progressive Mesangioproliferative Glomerulonephritis in the Rat

Contribution of collagen adhesion receptors to tissue fibrosis

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