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.

Keywords:
HIV-associated nephropathy, Matrix metalloproteinase-9, Real-time quantitative polymerase chain reaction
1.
Davies M, Martin J, Thomas GJ, Lovett DH: Proteinases and glomerular matrix turnover. Kidney Int 1992;41:671–678.
2.
Lenz Oliver, Elliot SJ, Setler-Stevenson WG: Matrix metalloproteinases in renal development and disease. J Am Soc Nephrol 2000;11:574–581.
3.
Matrisian LM: The matrix-degrading metalloproteinases. Bioessays 1992;14:455–463.
4.
Koide H, Nakamura T, Ebihara I, Tomino Y: Increased mRNA expression of metalloproteinase-9 in peripheral blood monocytes from patients with immunoglobulin A nephropathy. Am J Kidney Dis 1996;28:32–39.
5.
Ebihara I, Nakamura T, Shimada N, Koide H: Increased plasma metalloproteinase-9 concentrations precede development of microalbuminuria in non-insulin-dependent diabetes mellitus. Am J Kidney Dis 1998;32:544–550.
6.
McMillan JI, Riordan JW, Couser WG, Pollock AS, Lovett DH: Characterization of a glomerular epithelial cell metalloproteinase as a matrix metalloproteinase-9 with enhanced expression in a model of membranous glomerulonephritis. J Clin Invest 1996;97:1094–1101.
7.
Barisoni L, Szabolcs M, Ward L, D’Agati V: Visceral epithelial cell alterations in focal segmental glomerulosclerosis. Mod Pathol 1994;7:157–163.
8.
Fries JW, Sandstrom DJ, Meyer TW, Renneke HG: Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Invest 1989;60:205–218.
9.
Kriz W, Gretz N, Lemley KV: Progression of glomerular disease: Is the podocyte the culprit ? Kidney Int 1998;54:687–697.
10.
Rennke HG: How does glomerular epithelial cell injury contribute to progressive glomerular damage? Kidney Int Suppl 1994;45:S58–S63.
11.
Ahuja TS, M Borucki, M Funtanilla, V Shahinian, M Hollander, S Rajaraman: Is the prevalence of HIV-associated nephropathy decreasing? Am J Nephrol 1999;19:655–659.
12.
D’Agati V, Suh JI, Carbone L, Cheng JT, Appel G: Pathology of HIV-associated nephropathy: A detailed morphologic and comparative study. Kidney Int 1989;35:1358–1370.
13.
Barisoni L, Kriz W, Mundel P, D’Agati V: The dysregulated podocyte phenotype: A novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 1999;10:51–61.
14.
Stanta G, Schneider C: RNA extracted from paraffin-embedded human tissue is amenable to analysis by PCR amplification. Biotechniques 1991;11:304–308.
15.
Stanta G, Bonin S, Perin R: RNA extraction from formalin-fixed and paraffin-embedded tissues. Methods Mol Biol 1998;86:284–295.
16.
Godfrey TE, Kim SH, Chavira M, Ruff DW, Warren RS, Gray JW, Jensen RH: Quantitative mRNA expression analysis from formalin-fixed, paraffin-embedded tissues using 5′ nuclease quantitative reverse transcription-polymerase chain reaction. J Mol Diagn 2000;2:84–91.
17.
Lee LG, Connell CR, Bloch W: Allelic discrimination by nick-translation PCR with fluorogenic probes. Nucleic Acids Res 1993;21:3761–3766.
18.
Campbell CE, Flenniken AM, Skup D, Williams BRG: Identification of a serum and phorbol ester-responsive element in the murine tissue inhibitor of metalloproteinase gene. J Biol Chem 1991;266:7199–7206.
19.
Yamamato T, Noble NA, Miller DE, Gold LI, Hishida A, Nagase M, Cohen AH, Border WA: Increased levels of transforming growth factor-beta in HIV-associated nephropathy. Kidney Int 1992;55:579–592.
20.
Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Dochertry AJ, Angel P, Heath JK: Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J 1987;6:1899–1904.
21.
Carome MA, Striker LJ, Peten EP, Moore J, Yang CW, Stevenson WG, Striker GE: Human glomeruli express TIMP-1 mRNA and TIMP-2 protein and mRNA. Am J Physiol 1993;264:F923–F929.
22.
Jones CL, Buch S, Post M, McCulloch L, Liu E, Eddy AA: Pathogenesis of interstitial fibrosis in chronic purine aminonucleoside nephrosis. Kidney Int 1991;40:1020–1031.
23.
Reckelhoff JF, Tygart VL, Racusen LC, Dzielak DJ: STZ-induced diabetes results in decreased activity of glomerular cathepsin and metalloproteinase in rats. Diabetes 1993;42:1425–1432.
24.
Del Prete D, Anglani F, Forino M, Ceol M, Fioretto P, Nosadini R, Baggio B, Gambaro G: Downregulation of glomerular matrix metalloproteinase-2 gene in human NIDDM. Diabetologia 1997;4:1449–1454.
25.
Steinmann-Niggli K, Ziswiler R, Kung M, Marti HP: Inhibition of matrix metalloproteinases attenuates anti-Thy 1.1 nephritis. J Am Soc Nephrol 1998;9:397–407.
26.
Lovett DH, Johnson RJ, Marti HP, Martin J, Davies M, Couser WG: Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis. Am J Pathol 1992;141:85–98.
27.
Bruggeman LA, Ross MD, Tanji N, Cara A, Dikman S, Gordon RE, Burns GC, D’Agati VD, Winston JA, Klotman ME, Klotman PE: Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol 2000;11:2079–2087.
28.
Nelson PJ, Gelman IH, Klotman PE: Suppression of HIV-1 expression by inhibitors of cyclin-dependent kinases promotes differentiation of infected podocytes. J Am Soc Nephrol 2001;12:2827–2831.
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2004
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