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      The Cyclin-Dependent Kinase Inhibitor p21 Limits Murine Mesangial Proliferative Glomerulonephritis

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          Abstract

          Background: Mesangial cell (MC) proliferation underlies increased matrix accumulation in glomerulonephritis (GN), and the resolution of MC proliferation occurs largely through apoptosis. Proliferation and apoptosis are controlled by specific cell cycle proteins, where cyclin-dependent kinase (CDK) inhibitors such as p21 bind target cyclin-CDK complexes. However, the role of p21 in acute mesangial proliferative GN is not known. This study was conducted to test the hypothesis that p21 regulates MC proliferation and apoptosis in anti-MC serum-induced GN. Methods: Age and sex matched wild-type (p21+/+) and p21-deficient (p21–/–) mice were injected with sheep anti-MC serum. Renal function (BUN, urinary albumin excretion), histology, DNA synthesis (BrdU. Ki-67) and apoptosis (TUNEL) were quantified at day 6 and day 12 (n = 6–8/time point). Results: In p21+/+ mice, anti-MC-serum induced mild MC proliferative GN, and glomerular p21 expression was increased. Renal function was worse in nephric p21–/– mice. PAS and silver staining revealed that p21–/– mice had typical features of MC proliferative GN with focal segmental tuft necrosis, focal mesangiolysis and focal mesangial hypercellularity. Occasional features of podocyte injury (swelling, vacuolization) were noted. Double immunostaining confirmed increased mesangial cell DNA synthesis in nephritic p21–/– mice at day 6. In contrast, there was no difference in glomerular apoptosis in nephritic p21+/+ and p21–/– mice at each time point. Glomerular lesions were accompanied by severe glomerular and tubulointerstitial fibrosis in p21–/– mice. Conclusions: This data shows that the CDK-inhibitor p21 regulates the MC proliferative response to immune-mediated injury. In contrast, p21 does not alter the apoptotic response, resulting in a delayed resolution in nephritic p21–/– mice.

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          Most cited references 16

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          Radiation-induced cell cycle arrest compromised by p21 deficiency.

          The protein p21 is a dual inhibitor of cyclin-dependent kinases and proliferating-cell nuclear antigen (PCNA), both of which are required for passage through the cell cycle. The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21 has also been implicated in cell senescence and in cell-cycle withdrawal upon terminal differentiation. Here we investigate the role of p21 in these processes using chimaeric mice composed partly of p21-/- and partly of p21+/+ cells. Immunohistochemical studies of the p21+/+ and p21-/- components of adult small intestine indicated that deletion of p21 has no detectable effect on the migration-associated differentiation of the four principal intestinal epithelial cell lineages or on p53-dependent apoptosis following irradiation. However, p21-/- mouse embryo fibroblasts are impaired in their ability to undergo G1 arrest following DNA damage.
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            Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure.

            The p21 protein is found in the nucleus of most cells at low levels and is induced to elevated levels after DNA damage, causing cell-cycle arrest. We have reported that p21 mRNA is rapidly induced to high levels in murine kidney after acute renal failure. The function(s) in the kidney of p21 induction in cisplatin-induced acute renal failure was studied with mice that are homozygous for a p21 gene deletion. After drug administration, as compared with their wild-type littermates, p21(-/-) mice display a more rapid onset of the physiologic signs of acute renal failure, develop more severe morphologic damage, and have a higher mortality. Therefore, the induction of p21 after cisplatin administration is a protective event for kidney cells. Using both bromodeoxyuridine incorporation and nuclear proliferating cell nuclear antigen detection, we found that cisplatin administration caused kidney cells to start entering the cell-cycle. However, cell-cycle progression is inhibited in wild-type mice, whereas kidney cells in the p21(-/-) mice progress into S-phase. We propose that p21 protects kidneys damaged by cisplatin by preventing DNA-damaged cells from entering the cell-cycle, which would otherwise result in death from either apoptosis or necrosis.
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              The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development.

              Here we show that the cell-cycle regulator p21 is involved in immune system function. T lymphocytes from p21-/- mice exhibit significant proliferative advantage over wild-type cells following prolonged stimulation, but not after primary activation. Consistent with this, p21-deficient mice accumulate abnormal amounts of CD4+ memory cells, and develop loss of tolerance towards nuclear antigens. Similar to human lupus, female p21-deficient mice develop antibodies against dsDNA, lymphadenopathy, and glomerulonephritis, leading to decreased viability. These data demonstrate a specialized role for p21 in the control of T-cell proliferation, tolerance to nuclear antigens, and female-prone lupus. These findings could be the basis for new therapeutic approaches to lupus.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2006
                January 2006
                22 September 2005
                : 102
                : 1
                : e8-e18
                Affiliations
                aDivision of Nephrology and bDepartment of Pathology, University of Washington, Seattle, Wash.; cNIH, Bethesda, Md., USA; dDepartment of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
                Article
                88311 Nephron Exp Nephrol 2006;102:e8–e18
                10.1159/000088311
                16179805
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, References: 24, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/88311
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Glomerulonephritis, Cyclin kinase inhibitor, p21, Cell cycle

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