Blood pressure influences end-stage renal disease of Cd151 knockout mice

Sachs, Norman; Claessen, Nike; Aten, Jan; Kreft, Maaike; Teske, Gwendoline J. D.; Koeman, Anneke; Zuurbier, Coert J.; Janßen, Hans; Sonnenberg, Arnoud

doi:10.1172/jci65883

Cited by 17 publications

(26 citation statements)

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“…11 The mechanisms for these glomerular abnormalities are well defined using laminin-binding integrin and CD151-null mice. 4,12 CD151-null mice present with FSGS, similar to that observed in humans carrying nonsense mutations in CD151. The degree of glomerulosclerosis in these mice is similar to that of mice lacking the integrin a3 subunit in podocytes and is related to podocyte loss.…”

Section: The Laminin Receptorssupporting

confidence: 67%

Integrins in Kidney Disease

Pozzi

Zent²

2013

Journal of the American Society of Nephrology

107

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A major hallmark of chronic kidney injury is fibrosis, which is characterized by increased accumulation of extracellular matrix components that replace the damaged tissue. Normally, the synthesis and degradation of extracellular matrix components are finely regulated; however, when matrix replacement goes unchecked, there is unwanted and irreversible tissue scarring with consequent organ damage, organ failure, and, in certain cases, death. Many factors, including cell-matrix interactions, play a role in the development of renal fibrosis. Cell-matrix interactions are made possible by integrins, a family of transmembrane receptors that, upon binding to the extracellular matrix, activate intracellular signaling. Thus, they control various cell functions, including survival, proliferation, migration, and matrix homeostasis. Genetic mutations in humans and the development of animal models lacking integrins in selective parts of the kidney have improved our understanding of molecular mechanisms and pathways controlling matrix remodeling in kidney disease. Here we outline the major integrins involved in kidney disease and some of the major molecular mechanisms whereby integrins contribute to kidney fibrosis.

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Section: The Laminin Receptorssupporting

confidence: 67%

Integrins in Kidney Disease

Pozzi

Zent²

2013

Journal of the American Society of Nephrology

107

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“…[27][28][29] Global or podocyte-specific deletion of either subunit leads to proteinuria and early death in animals. 28,29,49 Additionally, we and others have recently shown that podocyte injury leads to reduced levels of active b1 in mice and patients, 30,33 which suggests that preventing loss of active b1-integrin levels in podocytes might be protective. Using novel small molecule agonists of b2 integrin CD11b/CD18, we have previously shown that such pharmacologic activation of integrins in vivo is a new, therapeutically relevant mechanism for targeting this family of adhesion receptors.…”

Section: Discussionmentioning

confidence: 90%

A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules

Lee¹,

Khan²,

Faridi³

et al. 2015

Journal of the American Society of Nephrology

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Podocyte injury and loss mark an early step in the pathogenesis of various glomerular diseases, making these cells excellent targets for therapeutics. However, cell-based high-throughput screening assays for the rational development of podocyte-directed therapeutics are currently lacking. Here, we describe a novel high-content screening-based phenotypic assay that analyzes thousands of podocytes per assay condition in 96-well plates to quantitatively measure dose-dependent changes in multiple cellular features. Our assay consistently produced a Z9 value .0.44, making it suitable for compound screening. On screening with .2100 pharmacologically active agents, we identified 24 small molecules that protected podocytes against injury in vitro (1% hit rate). Among the identified hits, we confirmed an b1-integrin agonist, pyrintegrin, as a podocyte-protective agent. Treatment with pyrintegrin prevented damage-induced decreases in F-actin stress fibers, focal adhesions, and active b1-integrin levels in cultured cells. In vivo, administration of pyrintegrin protected mice from LPS-induced podocyte foot process effacement and proteinuria. Analysis of the murine glomeruli showed that LPS administration reduced the levels of active b1 integrin in the podocytes, which was prevented by cotreatment with pyrintegrin. In rats, pyrintegrin reduced peak proteinuria caused by puromycin aminonucleoside-induced nephropathy. Our findings identify pyrintegrin as a potential therapeutic candidate and show the use of podocyte-based screening assays for identifying novel therapeutics for proteinuric kidney diseases.

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“…To date, it has been reported that CD151 KO mice have renal dysfunction (in the FVB strain) (26)(27)(28), impaired pathologic angiogenesis (15), delayed wound closure (29), and deficiencies in platelet aggregation (30). However, the involvement of CD151 in lung diseases remains unclear; this is the first report implicating CD151 in protection against pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 95%

Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity

Tsujino

Takeda

Arai

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. Objectives: To investigate the role of tetraspanin CD151 in pulmonary fibrosis. Methods: CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wildtype mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. Measurements and Main Results: A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased a-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. Conclusions: CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.Keywords: alveolar epithelial cell; adhesion strength; epithelial-tomesenchymal transition; Smad2; CD9 Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology; the condition has a poor prognosis, and there are no effective treatments. IPF is characterized by progressive deposition of collagen and other extracellular matrix (ECM) molecules (1). Previously, IPF was viewed as a "smoldering" inflammatory response that ultimately led to chronic lung injury with subsequent fibrosis. However, inflammation is now not regarded as crucial to the etiology, largely because current antiinflammatory therapies for IPF have provided little benefit for patients (2). Instead, it has become clear that abnormal behavior of alveolar epithelial cells (AECs) is a primary source of the development of pulmonary fibrosis (3, 4). The disease process is initiated through repetitive injury of AECs, causing AEC activation, which in turn leads to recruitment of immune cells and fibroblasts within the lung microenvironment. Aberrant activated AECs, in cooperation with migrated immune cells and fibroblasts, secrete and activate latent transforming growth factor (TGF)-b 1 , as well as other profibrotic factors, which promote the differentiation of fibroblasts and AECs to myofibroblasts, resulting in overproduction of ECM in the lung.The tet...

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Blood pressure influences end-stage renal disease of Cd151 knockout mice

Cited by 17 publications

References 0 publications

Integrins in Kidney Disease

Integrins in Kidney Disease

A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules

Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity

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