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      Matrix Metalloproteinase-9 Expression in Renal Biopsies of Patients with HIV-Associated Nephropathy

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          Abstract

          Background/Aims: The normal architecture and function of the kidney are maintained by a critical turnover of the extracellular matrix (ECM). Although increased synthesis of ECM leads to progression of renal failure, the role of degradation of ECM by metalloproteinases in progressive nephropathies is unclear. Recently, in an animal model of membranous glomerulonephritis (Heymann nephritis), visceral epithelial cell (VEC) injury has been found to rapidly increase matrix metalloproteinase-9 (MMP-9) synthesis by these cells during the period of maximal proteinuria. Because injury to glomerular VECs may be an important initiating factor in the pathogenesis of focal segmental glomerulosclerosis (FSGS), especially in HIV-associated nephropathy (HIVAN), we determined the expression of MMP-9 and its inhibitors in renal biopsies of patients with HIVAN. Methods: RNA was isolated from cortical renal tissue of 6 patients with HIVAN. Only those biopsies which displayed characteristic findings of HIVAN including collapsing FSGS, cystic dilatation of the tubules, and proliferation of VECs were used. As controls, we obtained renal cortical tissue from normal areas of kidneys removed due to malignancies. MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 mRNA expressions were determined using real-time quantitative reverse transcription-polymerase chain reaction. In all 6 patients with HIVAN, MMP-9 and TIMP-1 were overexpressed. We localized MMP-9 protein to the glomeruli with immunohistochemical detection. Conclusion: MMP-9 is overexpressed in the glomeruli of patients with HIVAN and may be involved in the pathogenesis of the disease.

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          Most cited references 3

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          Increased levels of transforming growth factor-beta in HIV-associated nephropathy.

          Human immunodeficiency virus-associated nephropathy (HIVAN) is a renal disease of unknown pathogenesis. Recent evidence suggests that the fibrogenic cytokine transforming growth factor-beta (TGF-beta) might be involved. We hypothesized that overproduction of TGF-beta in the kidney might be involved in the pathogenesis of HIVAN. The mRNA and protein expression of TGF-beta isoforms, TGF-beta 1, TGF-beta 2, and TGF beta 3, deposition of matrix proteins induced by TGF-beta, and levels of HIV Tat protein were studied in HIVAN. Controls included normal and diseased kidneys from HIV-positive and -negative patients. The ability of Tat to induce production of TGF-beta and matrix proteins was also studied in human mesangial cells. Normal kidneys, thin basement membrane nephropathy, and minimal change disease were negative for the three TGF-beta isoforms and Tat. In HIVAN, levels of TGF-beta isoforms and Tat were significantly increased, along with the expression of TGF-beta mRNA and deposition of matrix proteins stimulated by TGF-beta. Increased levels of TGF-beta isoforms, but not Tat, were also found in other glomerular diseases characterized by matrix accumulation. HIV infection, in the absence of HIVAN, was not associated with an increase in TGF-beta or Tat expression. Tat stimulated the expression and production of TGF-beta 1 and matrix proteins by human mesangial cells. Our findings suggest that overproduction of TGF-beta is involved in the pathogenesis of HIVAN.
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            Down-regulation of glomerular matrix metalloproteinase-2 gene in human NIDDM.

            Regulation of mesangial matrix deposition is a dynamic phenomenon involving synthetic and degradative processes. The latter involve a number of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP). Experimental studies suggest that mesangial matrix degradation is inhibited in diabetic nephropathy, and that this phenomenon has a pathogenic role. The expression of genes for MMP2 and TIMP2 in human diabetic nephropathy was investigated. Reverse transcription polymerase chain reaction was carried out in microdissected glomeruli and tubulo-interstitium obtained from kidney biopsies. We studied 16 NIDDM patients, 5 patients with glomerulonephritis or chronic kidney transplant rejection, and 5 normal control subjects. Albumin excretion rate and renal histology for NIDDM patients were available. Contrary to TIMP2 which was expressed both in tubulo-interstitium and glomeruli in almost all renal biopsies, MMP2 gene down-regulation was observed in glomeruli from all NIDDM patients, irrespective of the albumin excretion rate, and of renal histology. In contrast, this gene was expressed in biopsies from other subjects (chi(2) = 20.6; p = 0.000). In conclusion, this study demonstrates that: 1) in glomeruli of NIDDM patients the MMP2 gene is down-regulated; 2) in biopsies of NIDDM patients the MMP2/TIMP2 pattern is peculiar for NIDDM; 3) the MMP2 gene down-regulation is observed in all NIDDM patients, irrespective of the level of albuminuria and of renal histology. MMP2 gene down-regulation seems to be a molecular epiphenomenon of diabetes, rather than a marker of diabetic nephropathy.
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              Is the Prevalence of HIV-Associated Nephropathy Decreasing?

              Initial reports have suggested that approximately 10% of patients with HIV-infection develop HIV-associated nephropathy (HIVAN). It has also been predicted that by the end of the decade, HIVAN is likely to become a third leading cause of end-stage renal disease (ESRD) in African-Americans between the ages of 20–64 years. As the morbidity and mortality from HIV-infection has decreased in the last few years, it is possible that prevalence of HIVAN is also changing. We therefore screened HIV-1-infected patients followed in our hospital for HIVAN. A screening urinalysis was performed in 557 HIV-1-infected adult patients between March and May 1998. Of these, 252 were outpatients and 305 were Texas Department of Criminal Justice inmates (TDCJI). Demographic and laboratory data of these patients was obtained from the HIV patients’ database. Fifty percent of the patients were African-American, 36.6% were Caucasian and 12.7% were Hispanic. The mean age of patients was 37 ± 8 years. Seventy-nine percent of the patients were males and a history of intravenous drug abuse (IVDA) was present in 28%. Twenty-three percent of the patients were concomitantly infected with hepatitis C virus, 4.1% were positive for hepatitis B surface antigen, and rapid plasma reagin test for syphilis was positive in 9.1%. In 38 patients who had more than 100 mg/dl (2+) proteins on screening urinalysis, total urinary proteins were quantitated by collecting 24 h urine specimens. Fifteen of these patients had urinary proteins more than 1.5 g/day (12 patients >3.5 g/24 h and 3 patients >1.5 g/24 h). A renal biopsy was done in 14 of these patients and clinical diagnosis of HIVAN was made in one patient who refused biopsy. Renal biopsies revealed HIVAN [9], diabetic nephropathy [2], membranoproliferative glomerulonephritis [2], Fibrillary glomerulonephritis [1]. All 10 patients (5 TDCJI and 5 outpatients) with HIVAN were African-American. Two of these 10 patients had a history of IVDA and another two were concomitantly infected with hepatitis C virus. The plasma viral load (Pvl) and total CD4 count was not different in patients with or without HIVAN [(Pvl log 10.05 ± 1.39 vs. 9.9 ± 2.18 copies/ml, p = 0.78) (CD4: 187 ± 192 vs. 288 ± 249 cells/μl, p = 1.17) mean ± SD]. We conclude that in our HIV-infected population HIVAN exclusively affected African-Americans and the prevalence in them was 3.5%.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2003
                November 2003
                17 November 2004
                : 95
                : 3
                : c100-c104
                Affiliations
                aDepartment of Medicine, Division of Nephrology, University of Texas Medical Branch, Galveston, Tex., and bDepartment of Integrative Biology, University of Texas Health Science Center at Houston, Houston Tex., USA
                Article
                74323 Nephron Clin Pract 2003;95:c100–c104
                10.1159/000074323
                14646370
                © 2003 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: 2, References: 28, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/74323
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