Judith S Bond

Christian-Albrechts-Universität zu Kiel, Kiel, Schleswig-Holstein, Germany

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Publications (51)205.95 Total impact

  • Timothy R Keiffer, Judith S Bond
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    ABSTRACT: Meprins have been implicated in the pathogenesis of several inflammatory diseases including inflammatory bowel disease, in which the cytokine interleukin-6 (IL-6) is a prominent effector molecule. Because IL-6 levels are markedly elevated in meprin α and α/β knockout mice in an experimental model of IBD, the interaction between meprins and IL-6 were studied. The results demonstrate that rodent and human meprin A and B cleave IL-6 to a smaller product and subsequently are capable of extensive degradation of the cytokine. Analysis of the limited degradation product formed by meprin A indicated that 3-5 amino acids are removed from the C-terminus of the cytokine. Meprin A and meprin B cleaved IL-6 with micromolar affinities (Km of 4.7 and 12.0 uM, respectively) and with high efficiencies (kcat/Km of 0.2 and 2.5 (M-1 s-1) x 106 , respectively). These efficiency constants are among the highest for known meprin substrates. Madin-Darby Canine Kidney Cells transiently transfected with meprin α or meprin β constructs also cleave exogenous IL-6. Both human and murine IL-6 cleaved by meprin A or B are inactivated, as demonstrated by their decreased capability to stimulate proliferation of B9 cells. These results are consistent with the proposition that one function of meprin metalloproteinases is to modulate inflammation by inactivating IL-6.
    Journal of Biological Chemistry 01/2014; · 4.65 Impact Factor
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    ABSTRACT: The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a two-layered mucus system where the inner mucus is attached to the epithelium, whereas the small intestine normally has a nonattached mucus. However, the mucus of the small intestine of meprin {beta}-deficient mice was now found to be attached. Meprin {beta} is an endogenous zinc-dependent metalloprotease now shown to cleave the N-terminal region of the MUC2 mucin at two specific sites. When recombinant meprin {beta} was added to the attached mucus of meprin {beta}-deficient mice, the mucus was detached from the epithelium. Similar to meprin {beta}-deficient mice, germ-free mice have attached mucus as they did not shed the membrane-anchored meprin {beta} into the luminal mucus. The ileal mucus of cystic fibrosis (CF) mice with a nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channel was recently shown to be attached to the epithelium. Addition of recombinant meprin {beta} to CF mucus did not release the mucus, but further addition of bicarbonate rendered the CF mucus normal, suggesting that MUC2 unfolding exposed the meprin {beta} cleavage sites. Mucus is thus secreted attached to the goblet cells and requires an enzyme, meprin {beta} in the small intestine, to be detached and released into the intestinal lumen. This process regulates mucus properties, can be triggered by bacterial contact, and is nonfunctional in CF due to poor mucin unfolding.
    PNAS. 01/2014; 1:1407597111-.
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    ABSTRACT: Type I fibrillar collagen is the most abundant protein in the human body, crucial for the formation and strength of bones, skin, and tendon. Proteolytic enzymes are essential for initiation of the assembly of collagen fibrils by cleaving off the propeptides. We report that Mep1a(-/-) and Mep1b(-/-) mice revealed lower amounts of mature collagen I compared with WT mice and exhibited significantly reduced collagen deposition in skin, along with markedly decreased tissue tensile strength. While exploring the mechanism of this phenotype, we found that cleavage of full-length human procollagen I heterotrimers by either meprin α or meprin β led to the generation of mature collagen molecules that spontaneously assembled into collagen fibrils. Thus, meprin α and meprin β are unique in their ability to process and release both C- and N-propeptides from type I procollagen in vitro and in vivo and contribute to the integrity of connective tissue in skin, with consequent implications for inherited connective tissue disorders.
    Proceedings of the National Academy of Sciences 08/2013; · 9.81 Impact Factor
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    ABSTRACT: Meprin metalloproteases are highly expressed at the luminal interface of the intestine and kidney and in certain leukocytes. Meprins cleave a variety of substrates in vitro including extracellular matrix proteins, adherens junction proteins and cytokines, and have been implicated in a number of inflammatory diseases. The linkage between results in vitro and pathogenesis however, has not been elucidated. The current study aimed to determine whether meprins are determinative factors in disrupting the barrier function of the epithelium. Active meprin A or meprin B applied to the Madin-Darby canine kidney (MDCK) cell monolayers increased permeability to fluorescein isothiocyanate (FITC)-dextran and disrupted immunostaining of the tight junction protein occludin but not claudin-4. Meprin A, but not meprin B, cleaved occludin in MDCK monolayers. Studies with recombinant occludin demonstrated meprin A cleaves the protein between Gly100 and Ser101 on the first extracellular loop. In vivo experiments demonstrated that meprin A infused into the mouse bladder increased the epithelium permeability to sodium fluorescein. Furthermore, monocytes from meprin knockout (KO) mice on the C57BL/6 background were less able to migrate through an MDCK monolayer than monocytes from wild-type (WT) counterparts. These results demonstrate the capability of meprin A to disrupt epithelial barriers and implicate occludin as one of the important targets of meprin A that may modulate inflammation.
    AJP Renal Physiology 06/2013; · 4.42 Impact Factor
  • Proteases Structure and Function, DOI 10.1007/978-3-7091-0885-7_11 edited by K. Brix and W. Stoecker, 01/2013: chapter 11; Springer Verlag.
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    ABSTRACT: Meprins are multimeric proteases that are implicated in inflammatory bowel disease (IBD) by both genetic association studies and functional studies in knockout mice. Patients with IBD show decreased colonic expression of meprin α, though regulation of expression, particularly under inflammatory stimuli, has not been studied. The studies herein demonstrate that the human meprin α transcript is bound and stabilized by HuR at baseline, and that treatment with the inflammatory stimulus phorbol 12-myristate 13-acetate (PMA) downregulates meprin α expression by inducing TTP. The enhanced binding of TTP to the MEP1A 3' UTR results in destabilization of the transcript, and occurs at a discrete site from HuR. This is the first report to describe a mechanism for post-transcriptional regulation of meprin α, and will help clarify the role of meprins in the inflammatory response and disease.
    Journal of Biological Chemistry 12/2012; · 4.65 Impact Factor
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    ABSTRACT: The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)-the constitutive α-secretase-is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin(-/-) mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.
    Cellular and Molecular Life Sciences CMLS 09/2012; · 5.62 Impact Factor
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    ABSTRACT: Meprins, metalloproteinases abundantly expressed in the brush-border membranes (BBMs) of rodent proximal kidney tubules, have been implicated in the pathology of renal injury induced by ischemia-reperfusion (IR). Disruption of the meprin β gene and actinonin, a meprin inhibitor, both decrease kidney injury resulting from IR. To date, the in vivo kidney substrates for meprins are unknown. The studies herein implicate villin and actin as meprin substrates. Villin and actin bind to the cytoplasmic tail of meprin β, and both meprin A and B are capable of degrading villin and actin present in kidney proteins as well as purified recombinant forms of these proteins. The products resulting from degradation of villin and actin were unique to each meprin isoform. The meprin B cleavage site in villin was Glu(744)-Val(745). Recombinant forms of rat meprin B and homomeric mouse meprin A had K(m) values for villin and actin of ∼1 μM (0.6-1.2 μM). The k(cat) values varied substantially (0.6-128 s(-1)), resulting in different efficiencies for cleavage, with meprin B having the highest k(cat)/K(m) values (128 M(-1)·s(-1) × 10(6)). Following IR, meprins and villin redistributed from the BBM to the cytosol. A 37-kDa actin fragment was detected in protein fractions from wild-type, but not in comparable preparations from meprin knockout mice. The levels of the 37-kDa actin fragment were significantly higher in kidneys subjected to IR. The data establish that meprins interact with and cleave villin and actin, and these cytoskeletal proteins are substrates for meprins.
    AJP Renal Physiology 07/2011; 301(4):F871-82. · 4.42 Impact Factor
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    ABSTRACT: Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin β is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin β and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin β. Processing of APP by meprin β was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin β(-/-) mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin β is a physiologically relevant enzyme in APP processing.
    Journal of Biological Chemistry 06/2011; 286(31):27741-50. · 4.65 Impact Factor
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    ABSTRACT: Identification of physiologically relevant substrates is still the most challenging part in protease research to understand the biological activity of these enzymes. The zinc-dependent metalloprotease meprin β is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin β and the amyloid precursor protein (APP). Although APP is intensively studied as an ubiquitously expressed cell surface protein which is involved in Alzheimer's disease, its precise physiological role and relevance remains elusive. Based on a novel proteomics technique termed TAILS (Terminal Amine Isotopic Labeling of Substrates), APP was identified as a substrate for meprin β. Processing of APP by meprin β was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates, but not in meprin β-/- mouse brain lysates. Although, these APP fragments were in the range of those responsible for caspase induced neurodegeneration we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin β is a physiologically relevant enzyme in APP processing.
    Journal of Biological Chemistry 06/2011; · 4.65 Impact Factor
  • Judith S. Bond, Timothy R. Keiffer, Qi Sun
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    ABSTRACT: The immediate environment of cells is a rich source of proteolytic enzymes due to plasma membrane and secreted proteases, and many important physiological and pathological processes take place pericellularly. Meprin metalloproteases that are membrane-bound and secreted act pericellularly to modify proteins and peptides, and there is increasing evidence that these modifications have important implications in the hematological and immune systems.
    04/2011: pages 75-94;
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    ABSTRACT: The Epithelial Na(+) Channel (ENaC) is an apical heteromeric channel that mediates Na(+) entry into epithelial cells from the luminal cell surface. ENaC is activated by proteases that interact with the channel during biosynthesis or at the extracellular surface. Meprins are cell surface and secreted metalloproteinases of the kidney and intestine. We discovered by affinity chromatography that meprins bind γ-ENaC, a subunit of the ENaC hetero-oligomer. The physical interaction involves NH(2)-terminal cytoplasmic residues 37-54 of γ-ENaC, containing a critical gating domain immediately before the first transmembrane domain, and the cytoplasmic COOH-terminal tail of meprin β (residues 679-704). This potential association was confirmed by co-expression and co-immunoprecipitation studies. Functional assays revealed that meprins stimulate ENaC expressed exogenously in Xenopus oocytes and endogenously in epithelial cells. Co-expression of ENaC subunits and meprin β or α/β in Xenopus oocytes increased amiloride-sensitive Na(+) currents approximately two-fold. This increase was blocked by preincubation with an inhibitor of meprin activity, actinonin. The meprin-mediated increase in ENaC currents in oocytes and epithelial cell monolayers required meprin β, but not the α subunit. Meprin β promoted cleavage of α and γ-ENaC subunits at sites close to the second transmembrane domain in the extracellular domain of each channel subunit. Thus, meprin β regulates the activity of ENaC in a metalloprotease-dependent fashion.
    Channels (Austin, Tex.) 01/2011; 5(1):14-22. · 1.91 Impact Factor
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    ABSTRACT: MEP1A, which encodes the α subunit of meprin metalloproteinases, is a susceptibility gene for inflammatory bowel disease (IBD), and decreased intestinal meprin-α expression is associated with enhanced IBD in humans. Mice lacking meprin α (α knockout, αKO) have more severe colitis induced by dextran sulfate sodium (DSS) than wild-type (WT) mice, indicating an anti-inflammatory role for meprin A. Previous studies and those herein indicate the meprin B has proinflammatory activities. Therefore, mice lacking both meprin A and B (dKO mice) were generated to determine how their combined absence alters the inflammatory response to DSS. Unchallenged dKO mice grow and reproduce normally and have no obvious abnormal phenotype, except for a slightly elevated plasma albumin in both males and females and a lower urine creatinine level in dKO males. Upon oral administration of 3.5% DSS, the dKO mice have more severe colitis than the WT and βKO mice but significantly less than the αKO mice. The dKO mice lose more weight and have elevated MPO and IL-6 activities in the colon compared with WT mice. Systemic inflammation, monitored by plasma nitric oxide levels, is absent in DSS-treated dKO mice, unlike WT mice. The severity of experimental IBD in dKO mice is intermediate between αKO and WT mice. The data indicate that the absence of meprin A aggravates chronic inflammation and the lack of meprin B affords some protection from injury. Manipulation of the expression of meprin gene products may have therapeutic potential.
    AJP Gastrointestinal and Liver Physiology 11/2010; 300(2):G273-82. · 3.65 Impact Factor
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    ABSTRACT: The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the alpha-subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P=0.0012-0.04), and one in the 3'-untranslated region (P=2 x 10(-7)) that displayed associations with UC. Moreover, meprin-alpha mRNA was decreased in inflamed mucosa of IBD patients. Meprin-alpha knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin-alpha expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.
    Mucosal Immunology 04/2009; 2(3):220-31. · 7.54 Impact Factor
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    Qi Sun, Hong-Jian Jin, Judith S Bond
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    ABSTRACT: Meprin metalloproteases are implicated in inflammatory bowel disease, which involves dysfunction of immune cells. However, the roles of meprins in the immune and hematological system remain uncharacterized. In this report, we demonstrate that meprins were expressed in the hematological system, and meprin alpha/beta null (alpha(-/-)/beta(-/-)) mice had decreased prevalence of resident monocytes and natural killer (NK) cells in blood, with a concomitant accumulation of inflammatory monocytes and NK cells in bone marrow. In contrast, T and B lymphocytes were not affected by meprin deficiency. In response to acute inflammation induced by intraperitoneal injection of thioglycollate, meprin-deficient mice exhibited higher body temperature than wild-type mice, which was correlated with retention of inflammatory monocytes, but persistent low prevalence of NK cells in blood. These results indicate that meprin metalloproteases play important roles in the homeostasis of monocytes and NK cells, and possibly are involved in egress of these two type cells from bone marrow and homing to the periphery. Our findings are the first report to demonstrate that metalloproteases affect homeostasis of leukocytes, which have important implications for understanding physiology of and pathogenesis in the hematological system.
    Experimental hematology 01/2009; 37(3):346-56. · 3.11 Impact Factor
  • Carlos López-Otín, Judith S Bond
    Journal of Biological Chemistry 11/2008; 283(45):30433-7. · 4.65 Impact Factor
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    ABSTRACT: Meprin metalloproteases, composed of alpha and/or beta subunits, consist of membrane-bound and secreted forms that are abundantly expressed in proximal tubules of the kidney as well as secreted into the urinary tract. Previous studies indicated that meprin metalloproteases play a role in pathological conditions such as ischemic acute renal failure and urinary tract infection. The aim of this work was to examine the role of meprins in endotoxemic acute renal failure using meprin alpha knockout (alphaKO), meprin beta knockout (betaKO), and wild-type (WT) mice. Differences among the responses of the genotypes were observed as early as 1 h after challenge with 2.5 mg/kg ip Escherichia coli LPS, establishing roles for meprins in the endotoxemic response. Meprin alphaKO mice displayed lower blood urea nitrogen levels and decreased nitric oxide levels, indicative of a decreased systemic response to LPS compared with WT and meprin betaKO mice. Serum cytokine profiles showed lower levels of IL-1beta and TNF-alpha in the meprin alphaKO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin alphaKO mice were also hyporesponsive to LPS administered to the bladder, exhibiting significantly less bladder edema, leukocyte infiltration, and bladder permeability than WT mice. These data indicate that meprin A contributes to the renal and urogenital pathogenesis of endotoxicity.
    American journal of physiology. Renal physiology 11/2008; 296(1):F135-44. · 3.61 Impact Factor
  • Sanjita Banerjee, Judith S Bond
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    ABSTRACT: Interleukin-18 (IL-18), a pro-inflammatory cytokine, is a key factor in inflammatory bowel disease (IBD). Caspase-1 activates this cytokine, but other proteases are likely involved in maturation. Because meprin metalloproteinases have been implicated in IBD, the interaction of these proteases with proIL-18 was studied. The results demonstrate that the meprin beta subunit of meprins A and B cleaves proIL-18 into a smaller 17-kDa product. The cleavage is at the Asn51-Asp52 bond, a site C-terminal to caspase-1 cleavage. The cleavage occurred in vitro with a Km of 1.3 microm and in Madin-Darby canine kidney cells transfected with meprin beta when proIL-18 was added to the culture medium. The product of meprin B cleavage of proIL-18 activated NF-kappaB in EL-4 cells, indicating that it was biologically active. To determine the physiological significance of the interactions of meprins with proIL-18, an experimental model of IBD was produced by administering dextran sulfate sodium (DSS) to wild-type and meprin beta knock-out (betaKO) mice, and the serum levels of active IL-18 were determined. DSS-treated meprin betaKO mice had lower levels of the active cytokine in the serum compared with wild-type mice. Furthermore, in meprin alphaKO mice, which express meprin beta but not alpha, active IL-18 was elevated in the serum of DSS-treated mice compared with wild-type mice, indicating that the meprin isoforms have opposing effects on the IL-18 levels in vivo. This study identifies proIL-18 as a biologically important substrate for meprin beta and implicates meprins in the modulation of inflammation.
    Journal of Biological Chemistry 10/2008; 283(46):31371-7. · 4.65 Impact Factor
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    ABSTRACT: The astacins are a subfamily of the metzincin superfamily of metalloproteinases. The first to be characterized was the crayfish enzyme astacin. To date more than 200 members of this family have been identified in species ranging from bacteria to humans. Astacins are involved in developmental morphogenesis, matrix assembly, tissue differentiation and digestion. Family members include the procollagen C-proteinase (BMP1, bone morphogenetic protein 1), tolloid and mammalian tolloid-like, HMP (Hydra vulgaris metalloproteinase), sea urchin BP10 (blastula protein) and SPAN (Strongylocentrotus purpuratus astacin), the 'hatching' subfamily comprising alveolin, ovastacin, LCE, HCE ('low' and 'high' choriolytic enzymes), nephrosin (from carp head kidney), UVS.2 from frog, and the meprins. In the human and mouse genomes, there are six astacin family genes (two meprins, three BMP1/tolloid-like, one ovastacin), but in Caenorhabditis elegans there are 40. Meprins are the only astacin proteinases that function on the membrane and extracellularly by virtue of the fact that they can be membrane-bound or secreted. They are unique in their domain structure and covalent subunit dimerization, oligomerization propensities, and expression patterns. They are normally highly regulated at the transcriptional and post-translational levels, localize to specific membranes or extracellular spaces, and can hydrolyse biologically active peptides, cytokines, extracellular matrix (ECM) proteins and cell-surface proteins. The in vivo substrates of meprins are unknown, but the abundant expression of these proteinases in the epithelial cells of the intestine, kidney and skin provide clues to their functions.
    Molecular Aspects of Medicine 09/2008; 29(5):309-28. · 10.38 Impact Factor
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    ABSTRACT: Meprins are membrane-bound and secreted metalloproteinases consisting of alpha- and/or beta-subunits that are highly expressed in mouse kidney proximal tubules. Previous studies have implied that the meprin alpha/beta-isoform is deleterious when renal tissue is subjected to ischemia-reperfusion (I/R). To delineate the roles of the meprin isoforms in renal disease, we subjected mice deficient in meprin-beta (KO) and their wild-type (WT) counterparts to I/R. WT mice were markedly more susceptible to renal injury after I/R than the meprin-beta KO mice as determined by blood urea nitrogen levels. Urinary levels of inflammatory cytokines IL-6 and KC (CXCL1) were significantly higher in WT compared with meprin-beta KO mice by 6 h post-I/R. At 96 h postischemia, kidney mRNA expression levels for tumor necrosis factor-alpha, transforming growth factor-beta, inducible nitric oxide synthase, and heat shock protein-27 were significantly higher in the WT than meprin-beta KO mice. For WT mice subjected to I/R, there was a rapid (3 h) redistribution of meprin beta-subunits in cells in S3 segments of proximal tubules, followed by shedding of apical cell membrane and detachment of cells. These studies indicate that meprin-beta is important in the pathogenesis of renal injury following I/R and that the redistribution of active meprin-alpha/beta is a major contributor to renal injury and subsequent inflammation.
    American journal of physiology. Renal physiology 04/2008; 294(3):F480-90. · 3.61 Impact Factor

Publication Stats

800 Citations
205.95 Total Impact Points

Institutions

  • 2012–2013
    • Christian-Albrechts-Universität zu Kiel
      • Institute of Biochemistry
      Kiel, Schleswig-Holstein, Germany
  • 2011
    • Johannes Gutenberg-Universität Mainz
      • Cell and Matrix Biology
      Mainz, Rhineland-Palatinate, Germany
  • 1999–2011
    • Pennsylvania State University
      • Department of Biochemistry and Molecular Biology
      University Park, MD, United States
  • 2008–2009
    • Penn State Hershey Medical Center and Penn State College of Medicine
      • • Pediatrics
      • • Biochemistry and Molecular Biology
      Hershey, PA, United States
    • University of Oviedo
      • Department of Biochemistry and Molecular Biology
      Oviedo, Asturias, Spain
    • Universität Bern
      • Institut für Biochemie und Molekulare Medizin
      Bern, BE, Switzerland
  • 2005
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States