DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria

Groß, Oliver; Beirowski, Bogdan; Harvey, Scott J.; McFadden, Catherine; Chen, Dilys; Tam, Stephanie; Thorner, Paul; Smyth, Neil; Addicks, Klaus; Bloch, Wilhelm; Ninomiya, Yoshifumi; Sado, Yoshikazu; Weber, Manfred; Vogel, Wolfgang F.

doi:10.1111/j.1523-1755.2004.00712.x

Cited by 92 publications

(77 citation statements)

References 30 publications

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“…[1][2][3] However, current evidence does not support a key role for DDR1 in renal development and physiology, in particular because transgenic mice lacking DDR1 present a close to normal renal phenotype in basal conditions. 11,19 In contrast, DDR1 has been established as an important contributor to a broad variety of pathologic processes, especially in cancer and inflammation, by promoting cell migration, invasion, and survival. 9,10,20 -23 In parallel, several in vitro and in vivo studies have shown that DDR1 was involved in crucial mechanisms leading to fibrogenesis.…”

Section: Discussionmentioning

confidence: 99%

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Guerrot

Kerroch

Placier

et al. 2011

The American Journal of Pathology

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The interactions between tubulointerstitial infiltrating cells and the extracellular matrix play an important role in regulating renal fibrosis. Discoidin domain receptor 1 (DDR1) is a nonintegrin tyrosine kinase receptor for collagen implicated in cell adhesion, proliferation, and extracellular matrix remodeling. We have previously demonstrated that transgenic mice lacking DDR1 are protected from hypertension-associated renal fibrosis. The purpose of this study was to determine the role of DDR1 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After 12 days of unilateral ureteral obstruction (UUO), kidney histopathologic and real-time quantitative PCR analyses were performed in DDR1 ؊/؊ and wild-type mice. DDR1 expression was strongly increased in the obstructed kidney. Wild-type mice developed important perivascular and interstitial inflammation and fibrosis. In comparison, DDR1 ؊/؊ mice displayed reduced accumulation of fibrillar collagen and transforming growth factor ␤ expression. F4/80 ؉ cell count and proinflammatory cytokines were remarkably blunted in DDR1 ؊/؊ obstructed kidneys. Leukocyte rolling and adhesion evaluated by intravital microscopy were not different between DDR1 ؊/؊ and wild-type mice. Importantly, macrophages isolated from DDR1 ؊/؊ mice presented similar M1/M2 polarization but displayed impaired migration in response to monocyte chemoattractant protein-1. Together, these data suggest that DDR1 plays an important role in the pathogenesis of renal disease via enhanced inflammation. Inhibition of DDR1 expression or activity may represent a novel therapeutic target against the progression of renal diseases. Renal fibrosis is the consequence of the accumulation of extracellular matrix (ECM) components, including collagen, in the kidney. In chronic kidney diseases, irrespective of the initiating cause, fibrotic lesions autoaggravate, leading to a progressive decrease in renal function. Despite growing interest, the pathophysiologic pathways responsible for the progression of renal fibrosis remain elusive. A better understanding of specific mechanisms that promote inflammation and ECM synthesis is of critical importance in this setting because such pathways are susceptible to being at the cornerstone of the initiation and the progression of fibrogenesis.Discoidin domain receptor 1 (DDR1) is a tyrosine kinase transmembrane receptor for collagen constitutively expressed in several cell types and organs, including the gastrointestinal tract, lung, and kidney. 1 In the mammalian kidney, DDR1 is predominantly expressed by vascular smooth muscle cells, mesangial cells, and epithelial cells in normal conditions. 2,3 On activation by binding to collagen I to VI and VIII, DDR1 regulates cell differentiation, adhesion, proliferation, and ECM remodeling. 4 -6 A number of studies have shown that DDR1 is implicated in carcinogenesis, inflammation, atherosclerosis, and fibrogenesis. [7][8][9][10][11][12] Consistent with an important pathogenetic role in vascular diseases, 8,[1...

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Section: Discussionmentioning

confidence: 99%

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Guerrot

Kerroch

Placier

et al. 2011

The American Journal of Pathology

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“…33 The bulging of the GBM and ballooning of the glomerular tuft are among the most striking pathologies in nephrin Y3F/Y3F mice, and analogous structures have been reported in mice lacking other podocyte proteins essential for binding to actin or the GBM. 29,[40][41][42][43][44] An additional characteristic of nephrin Y3F/Y3F animals is the disorganized patterning of foot processes. Process formation in podocytes shares biologic features of that within neurons, wherein common cytoskeletal elements and signaling proteins are used to generate elaborate cell-based projections.…”

Section: Discussionmentioning

confidence: 99%

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

New¹,

Martín²,

Scott

et al. 2016

JASN

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Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics. Nephrin tyrosine phosphorylation is altered in human and experimental renal diseases characterized by pathologic foot process remodeling, prompting the hypothesis that phosphonephrin signaling directly influences podocyte morphology. To explore this possibility, we generated and analyzed knockin mice with mutations that disrupt nephrin tyrosine phosphorylation and Nck1/2 binding (nephrin Y3F/Y3F mice). Homozygous nephrin Y3F/Y3F mice developed progressive proteinuria accompanied by structural changes in the filtration barrier, including podocyte foot process effacement, irregular thickening of the glomerular basement membrane, and dilated capillary loops, with a similar but later onset phenotype in heterozygous animals. Furthermore, compared with wild-type mice, nephrin Y3F/Y3F mice displayed delayed recovery in podocyte injury models. Profiling of nephrin tyrosine phosphorylation dynamics in wild-type mice subjected to podocyte injury indicated site-specific differences in phosphorylation at baseline, injury, and recovery, which correlated with loss of nephrin-Nck1/2 association during foot process effacement. Our results define an essential requirement for nephrin tyrosine phosphorylation in stabilizing podocyte morphology and suggest a model in which dynamic changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton.

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“…Deletion of DDR1 led to decreased collagen adhesion, migration of vascular smooth muscle cells, and enhanced proliferation of mesangial cells (Curat and Vogel, 2002;Hou et al, 2001). In addition, DDR1 knockout mice develop localized thickening of GBM and proteinuria, suggesting that collagen IV-DDR1 interaction plays an important role for structural integrity and filtration function in the kidney (Gross et al, 2004).…”

Section: Nonintegrin Receptorsmentioning

confidence: 99%

Mammalian collagen IV

Khoshnoodi

Pedchenko

Hudson

2008

Microscopy Res & Technique

543

487

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Four decades have passed since the first discovery of collagen IV by Kefalides in 1966. Since then collagen IV has been investigated extensively by a large number of research laboratories around the world. Advances in molecular genetics have resulted in identification of six evolutionary related mammalian genes encoding six different polypeptide chains of collagen IV. The genes are differentially expressed during the embryonic development, providing different tissues with specific collagen IV networks each having unique biochemical properties. Newly translated α-chains interact and assemble in the endoplasmic reticulum in a chain-specific fashion and form unique heterotrimers. Unlike most collagens, type IV collagen is an exclusive member of the basement membranes and through a complex inter-and intramolecular interactions form supramolecular networks that influence cell adhesion, migration, and differentiation. Collagen IV is directly involved in a number of genetic and acquired disease such as Alport's and Goodpasture's syndromes. Recent discoveries have also highlighted a new and direct role for collagen IV in the development of rare genetic diseases such as cerebral hemorrhage and porencephaly in infants and hemorrhagic stroke in adults. Years of intensive investigations have resulted in a vast body of information about the structure, function, and biology of collagen IV. In this review article, we will summarize essential findings on the structural and functional relationships of different collagen IV chains and their roles in health and disease.

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DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria

Cited by 92 publications

References 30 publications

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

Mammalian collagen IV

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