Inhibition of matrix metalloproteinases attenuates anti-Thy1.1 nephritis.
ABSTRACT There is accumulating evidence that matrix metallo-proteinases (MMP) play a prominent role in glomerular inflammatory diseases. The aim of the present study was to determine the anti-inflammatory effects of the synthetic MMP inhibitor BB-1101 in acute anti-Thy1.1 nephritis. Sixty-three male Wistar rats were studied: healthy rats (n = 9), treated healthy rats (n = 9), nephritic rats (n = 18), and treated nephritic rats (n = 27). BB-1101 therapy (30 mg/kg body wt per d) of nephritic animals was initiated either 2 d before (n = 18) or 2 d after (n = 9) disease induction. Renal histology was analyzed 11 d after induction of the nephritis, at the peak of MMP-2 production and total glomerular cellularity. Pretreatment of nephritic rats by BB-1101 resulted in a significant amelioration of glomerular histology, assessed by glomerular cellularity, extracellular matrix deposition, and size of glomerular cross-sections. These beneficial effects were less pronounced, but in part still significant, in animals treated by BB-1101 after induction of anti-Thy1.1 nephritis. Proteinuria, expressed as area under the curve of the protein:creatinine ratio versus time, was clearly decreased in both groups of treated nephritic rats. Healthy control rats were not affected by MMP inhibitor treatment. In summary, the present study demonstrates for the first time in vivo that mesangial cell proliferation can be effectively suppressed by MMP inhibition. Thus, MMP inhibition by synthetic compounds may represent a new approach to the therapy of mesangial cell-mediated forms of glomerulonephritis.
Article: Metalloprotease meprin beta in rat kidney: glomerular localization and differential expression in glomerulonephritis.[show abstract] [hide abstract]
ABSTRACT: Meprin (EC 220.127.116.11) is an oligomeric metalloendopeptidase found in microvillar membranes of kidney proximal tubular epithelial cells. Here, we present the first report on the expression of meprin beta in rat glomerular epithelial cells and suggest a potential involvement in experimental glomerular disease. We detected meprin beta in glomeruli of immunostained rat kidney sections on the protein level and by quantitative RT-PCR of laser-capture microdissected glomeruli on the mRNA level. Using immuno-gold staining we identified the membrane of podocyte foot processes as the main site of meprin beta expression. The glomerular meprin beta expression pattern was altered in anti-Thy 1.1 and passive Heymann nephritis (PHN). In addition, the meprin beta staining pattern in the latter was reminiscent of immunostaining with the sheep anti-Fx1A antiserum, commonly used in PHN induction. Using Western blot and immunoprecipitation assays we demonstrated that meprin beta is recognized by Fx1A antiserum and may therefore represent an auto-antigen in PHN. In anti-Thy 1.1 glomerulonephritis we observed a striking redistribution of meprin beta in tubular epithelial cells from the apical to the basolateral side and the cytosol. This might point to an involvement of meprin beta in this form of glomerulonephritis.PLoS ONE 02/2008; 3(5):e2278. · 4.09 Impact Factor
Article: Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages.[show abstract] [hide abstract]
ABSTRACT: Glomerulonephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Although substantial progress has been made in the identification of pathogenic triggers that result in autoantibody production, little is known about the pathogenesis of aggressive proliferative processes that lead directly to irreversible glomerular damage and compromise of renal function. In this study, we describe a model of polyinosinic: polycytidylic acid-accelerated lupus nephritis in NZB/W mice that is characterized by severe glomerular proliferative lesions with de novo crescent formation, findings that are linked with decreased survival and adverse outcomes in lupus. Proliferative glomerulonephritis was associated with infiltrating kidney macrophages and renal expression of IFN-inducible genes, matrix metalloproteinases (MMPs), and growth factors. Crescent formation and renal MMP and growth factor expression were dependent on renal macrophages that expressed Il10, MMPs, osteopontin, and growth factors, including Pdgfc and Hbegf. Infiltrating macrophages and renal MMP expression were induced by type I IFN. These findings reveal a role for type I IFNs and alternatively activated macrophages in aggressive proliferative lesions of lupus nephritis.Proceedings of the National Academy of Sciences 02/2010; 107(7):3012-7. · 9.68 Impact Factor
Article: Differential regulation of metzincins in experimental chronic renal allograft rejection: potential markers and novel therapeutic targets.[show abstract] [hide abstract]
ABSTRACT: Chronic renal allograft rejection is characterized by alterations in the extracellular matrix compartment and in the proliferation of various cell types. These features are controlled, in part by the metzincin superfamily of metallo-endopeptidases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase (ADAM) and meprin. Therefore, we investigated the regulation of metzincins in the established Fisher to Lewis rat kidney transplant model. Studies were performed using frozen homogenates and paraffin sections of rat kidneys at day 0 (healthy controls) and during periods of chronic rejection at day +60 and day +100 following transplantation. The messenger RNA (mRNA) expression was examined by Affymetrix Rat Expression Array 230A GeneChip and by real-time Taqman polymerase chain reaction analyses. Protein expression was studied by zymography, Western blot analyses, and immunohistology. mRNA levels of MMPs (MMP-2/-11/-12/-14), of their inhibitors (tissue inhibitors of metalloproteinase (TIMP)-1/-2), ADAM-17 and transforming growth factor (TGF)-beta1 significantly increased during chronic renal allograft rejection. MMP-2 activity and immunohistological staining were augmented accordingly. The most important mRNA elevation was observed in the case of MMP-12. As expected, Western blot analyses also demonstrated increased production of MMP-12, MMP-14, and TIMP-2 (in the latter two cases as individual proteins and as complexes). In contrast, mRNA levels of MMP-9/-24 and meprin alpha/beta had decreased. Accordingly, MMP-9 protein levels and meprin alpha/beta synthesis and activity were downregulated significantly. Members of metzincin families (MMP, ADAM, and meprin) and of TIMPs are differentially regulated in chronic renal allograft rejection. Thus, an altered pattern of metzincins may represent novel diagnostic markers and possibly may provide novel targets for future therapeutic interventions.Kidney International 02/2006; 69(2):358-68. · 6.61 Impact Factor