Severe Fibronectin-Deposit Renal Glomerular Disease in Mice Lacking Uteroglobin

Zhang, Zhongjian; Kundu, Gopal C.; Yuan, Chiun‐Jye; Ward, Jerrold M.; Lee, Eric J.; DeMayo, Francesco J.; Westphal, Heiner; Mukherjee, Anil B.

doi:10.1126/science.276.5317.1408

Cited by 122 publications

(169 citation statements)

References 39 publications

(7 reference statements)

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“…The proband's father died of cancer at 30 years of age. A heterozygous 2918AϾG mutation causing a Y973C change in repeat III 4 was found in the index case and in her affected daughter but not in the unaffected father ( Fig. 1 b and c and SI Fig.…”

Section: Resultsmentioning

confidence: 99%

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Mutations in FN1 cause glomerulopathy with fibronectin deposits

Castelletti

Donadelli

Banterla

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

126

116

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Glomerulopathy with fibronectin (FN) deposits (GFND)is an autosomal dominant disease with age-related penetrance, characterized by proteinuria, microscopic hematuria, hypertension, and massive glomerular deposits of FN that lead to end-stage renal failure. The genetic abnormality underlying GFND was still unknown. We hypothesized that mutations in FN1, which encodes FN, were the cause of GFND. In a large Italian pedigree with eight affected subjects, we found linkage with GFND at the FN1 locus at 2q32. We sequenced the FN1 in 15 unrelated pedigrees and found three heterozygous missense mutations, the W1925R, L1974R, and Y973C, that cosegregated with the disease in six pedigrees. The mutations affected two domains of FN (Hep-II domain for the W1925R and the L1974R, and Hep-III domain for the Y973C) that play key roles in FN-cell interaction and in FN fibrillogenesis. Mutant recombinant Hep-II fragments were expressed, and functional studies revealed a lower binding to heparin and to endothelial cells and podocytes compared with wild-type Hep-II and an impaired capability to induce endothelial cell spreading and cytoskeletal reorganization. Overall dominant mutations in FN1 accounted for 40% of cases of GFND in our study group. These findings may help understanding the pathogenesis of proteinuria and glomerular FN deposits in GFND and possibly in more common renal diseases such as diabetic nephropathy, IgA nephropathy, and lupus nephritis. To our knowledge no FN1 mutation causing a human disease was previously reported.genetics ͉ proteinuria ͉ extracellular matrix ͉ kidney ͉ podocytes

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Section: Resultsmentioning

confidence: 99%

“…However, the genetic abnormality underlying GFND was still unknown (3)(4)(5). By whole-genome linkage analysis in a large pedigree, a gene locus for GFND was mapped on 1q32, within a 4.1-cM interval that contains a cluster of genes involved in the regulation of complement activation (RCA) (6).…”

mentioning

confidence: 99%

Mutations in FN1 cause glomerulopathy with fibronectin deposits

Castelletti

Donadelli

Banterla

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

126

116

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“…It should be noted, however, that UG knockout mice have elevated plasma sPLA 2 activities [46]. The UG-deficient mice also manifest several phenotypes [46][47][48][49], suggesting a multifunctional nature of this protein. UG is present in alveolar and bronchial secretions and most likely protects the phospholipid component of lung surfactant by inhibiting the lung-specific sPLA 2 activity [50].…”

Section: Discussionmentioning

confidence: 99%

Lys 43 and Asp 46 in α-helix 3 of uteroglobin are essential for its phospholipase A2 inhibitory activity

Chowdhury¹,

Mantile-Selvaggi²,

Miele³

et al. 2002

Biochemical and Biophysical Research Communications

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Uteroglobin (UG) is an anti-inflammatory, secreted protein with soluble phospholipase A 2 (sPLA 2 )-inhibitory activity. However, the mechanism by which UG inhibits sPLA 2 activity is unknown. UG is a homodimer in which each of the 70-amino acid subunits forms four a-helices. We previously reported that sPLA 2 -inhibitory activity of UG may reside in a segment of a-helix 3 that is exposed to the solvent. In addition, it has been suggested that UG may inhibit sPLA 2 activity by binding and sequestering Ca þþ , essential for sPLA 2 activation. By site-specific mutation, we demonstrate here that Lys 43 Glu, Asp 46 Lys or a combination of the two mutations in the full-length, recombinant human UG (rhUG) abrogates its sPLA 2 -inhibitory activity. We demonstrate further that recombinant UG does not bind Ca þþ although when it is expressed with histidine-tag (H-tag) it is capable of binding Ca þþ . Taken together our results show that: (i) Lys 43 and Asp 46 in rhUG are critical residues for the sPLA 2 -inhibitory activity of UG and (ii) Ca þþ -sequestration by rhUG is not likely to be one of the mechanisms responsible for its sPLA 2 -inhibitory activity. Ó 2002 Elsevier Science (USA). All rights reserved.

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“…Moreover, we (18) and others (19) have previously demonstrated that overexpression of UG in cancer cells reverses their transformed phenotype and neoplastic potential. We also demonstrated that UG-knock-out (UG-KO) mice (16) are highly susceptible to lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a carcinogen in cigarette smoke (20). Previously, we reported that the UG gene is constitutively expressed at a high level in the lung epithelia (21).…”

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confidence: 99%

“…It is constitutively expressed in the lungs of all mammals, and targeted disruption of the UG gene in mice (16) increases susceptibility to pulmonary inflammation (17). Moreover, we (18) and others (19) have previously demonstrated that overexpression of UG in cancer cells reverses their transformed phenotype and neoplastic potential.…”

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confidence: 99%

Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs

Saha

Lee

Zhang

et al. 2010

Journal of Biological Chemistry

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Emerging evidence indicates a link between inflammation and cancer metastasis, but the molecular mechanism(s) remains unclear. Uteroglobin (UG), a potent anti-inflammatory protein, is constitutively expressed in the lungs of virtually all mammals. UG-knock-out (UG-KO) mice, which are susceptible to pulmonary inflammation, and B16F10 melanoma cells, which preferentially metastasize to the lungs, provide the components of a model system to determine how inflammation and metastasis are linked. We report here that B16F10 cells, injected into the tail vein of UG-KO mice, form markedly elevated numbers of tumor colonies in the lungs compared with their wild type littermates. Remarkably, UG-KO mouse lungs overexpress two calcium-binding proteins, S100A8 and S100A9, whereas B16F10 cells express the receptor for advanced glycation end products (RAGE), which is a known receptor for these proteins. Moreover, S100A8 and S100A9 are potent chemoattractants for RAGE-expressing B16F10 cells, and pretreatment of these cells with a blocking antibody to RAGE suppressed migration and invasion. Interestingly, in UG-KO mice S100A8/S100A9 concentrations in blood are lowest in tail vein and highest in the lungs, which most likely guide B16F10 cells to migrate to the lungs. Further, B16F10 cells treated with S100A8 or S100A9 overexpress matrix metalloproteinases, which are known to promote tumor invasion. Most notably, the metastasized B16F10 cells in UG-KO mouse lungs express MMP-2, MMP-9, and MMP-14 as well as furin, a pro-protein convertase that activates MMPs. Taken together, our results suggest that a lack of an anti-inflammatory protein leads to increased pulmonary colonization of melanoma cells and identify RAGE as a potential anti-metastatic drug target.It is estimated that more than 90% of human cancer deaths result from metastasis (1-8), a complex process in which the cells from a primary tumor successfully invade and colonize a distant organ (6 -9). It has long been suspected that a functional relationship exists between inflammation and cancer. Indeed, in 1863, Virchow observed that cancer develops at locations where chronic inflammation is present. This hypothesis is partly based on his assumption that some substances that cause tissue injury and inflammation also enhance cell proliferation (10). Although it is clear now that proliferation alone does not account for cancer, the cause and effect relationship between inflammation and cancer is widely accepted. Nonetheless, many aspects of the molecular and cellular mechanisms that link inflammation, migration, and establishment of tumor colonies in a distant organ remain unresolved (5). Recently, it has been reported that a tumor microenvironment actively contributes to cancer initiation, progression, and metastasis (11, 12). It has also been suggested that reductions in the rates of cancer morbidity and mortality may be achieved by gaining greater understanding of the molecular mechanism(s) of tumor cell migration, invasion, and establishment of colonies (13). In this regard...

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Severe Fibronectin-Deposit Renal Glomerular Disease in Mice Lacking Uteroglobin

Cited by 122 publications

References 39 publications

Mutations in FN1 cause glomerulopathy with fibronectin deposits

Mutations in FN1 cause glomerulopathy with fibronectin deposits

Lys 43 and Asp 46 in α-helix 3 of uteroglobin are essential for its phospholipase A2 inhibitory activity

Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs

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