Mesangial cell apoptosis induced by a fibronectin fragment |
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Authors: | Y Nishizawa F Fukai Y Natori R Kato S Tanuma T Katayama |
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Institution: | (1) Department of Patho-Physiology and Clinical Development & Regulatory Affair Division, Development Department, Novartis Pharma K. K., 4-17-30, Nishi Azabu, Minato-Ku, Tokyo, 106, Japan;(2) Department of Patho-Physiology and Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12 Ichigaya Funagawara-Machi, Sinjuku-Ku, Tokyo, 162, Japan;(3) Department of Patho-Physiology and Division of Clinical Pharmacology, Research Institute, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku-Ku, Tokyo, 162, Japan |
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Abstract: | We previously showed that in passive Heymann nephritis (PHN) rats, a large quantity of fibronectin (FN) fragments containing the central cell-binding (CCB) domain and adjacent domains are generated in the kidney and excreted into urine (Nishizawa et al., Biol Pharm Bull 1998; 21: 429–433). To ascertain whether the FN fragments could affect the progression of PHN, we investigated the effect of a 150 K FN fragment containing the CCB and carboxyl-terminal heparin-binding (Hep 2) domains on cultured rat mesangial cells. When rat mesangial cells cultured on FN-coated plates were exposed to the 150 K FN fragment, some mesangial cells detached from the FN substrate and then underwent apoptosis as judged by nuclear and DNA fragmentations. The 150 K FN fragment competitively inhibited the mesangial cell adhesion to the FN substrate in a dose-dependent manner. Furthermore, gelatinzymography of the conditioned medium of mesangial cells showed that the 150 K FN fragment induced and/or poteintiated the extracellular matrix (ECM)-degrading proteinases including matrix metalloproteinases (MMPs) of mesangial cells. These results indicate that the 150 K FN fragment may elicit mesangial cell apoptosis by disrupting the mesangial cell adhesion through two distinct ways: the inhibition of mesangial cell adhesion and the ECM-degradation by the 150 K FN fragment-induced MMPs. Thus, FN fragments containing the CCB and adjacent domains generated in the kidneys of PHN rats may be involved in the evolution of the renal injury. |
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Keywords: | Apoptosis cell adhesion fibronectin fragment matrix metalloproteinase mesangial cell |
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