Role for Macrophage Metalloelastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome

Rao, Velidi H.; Meehan, Daniel T.; Delimont, Duane; Nakajima, Motowo; Wada, Takashi; Gratton, Michael Ann; Cosgrove, Dominic

doi:10.2353/ajpath.2006.050896

Cited by 78 publications

(86 citation statements)

References 53 publications

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“…In the present study, we clarified that MMP-12 was expressed in the podocytes of the ICGN strain and that no infiltrating macrophage was observed in glomeruli. These findings were similar to those for Alport syndrome mice in which the elevated MMP-12 expression may play a key contributory role in the progression of GBM pathogenesis [16]. Therefore, we speculate that the glomerular expression of MMP-12 involves the GBM's degradation and dysmorphology in the ICGN strain, and causes a worsening proteinuria.…”

Section: Discussionsupporting

confidence: 71%

“…It has been reported that MMP-12 is mainly produced by macrophages infiltrating tissues in which damage has occurred or remodeling is occurring, and helps to break down the components of the ECM [4-8, 17, 18, 24, 26], but its function in the kidneys remains unknown. Infiltrating macrophages produced MMP-12 in glomeruli of anti-GBM nephritis mice [5] and podocytes were the source of MMP-12 expression in glomeruli of Alport syndrome mice [16]. In the present study, we clarified that MMP-12 was expressed in the podocytes of the ICGN strain and that no infiltrating macrophage was observed in glomeruli.…”

Section: Discussionsupporting

confidence: 50%

“…cDNA was subjected to reverse transcription from 1 g of total RNA by using oligo-dT primer and SuperScript III (Invitrogen, Carlsbad, CA). The primer sequences were as follows [16]: MMP-12 (Forward: 5'-AAG CAA CTG GGC AAC TGG ACA ACT C-3'; Reverse: TGG TGA CAG AAA GTT GAT GGT GGA C-3', with an expected PCR product size of 630 bp), MCP-1 (Forward: 5'-AGA GAG CCA GAC GGA GGA AG-3'; Reverse: 5'-GTC ACA CTG GTC ACT CCT AC-3', with an expected PCR product size of 333 bp) and glucose 3-phosphate dehydrogenase (G3PDH Forward: 5'-ACC ACA GTC CAT GCC ATC AC-3'; Reverse; 5'-TCC ACC ACC CTG TTG CTG TA-3', with an expected PCR product size of 452 bp). The cycling conditions were as follows: at 94C for 5 min., then 35 cycles at 94C for 30 sec., 60C 30 sec., and 72C 45 sec., and finally 1 cycle at 72C for 7 min.…”

Section: Synthesis and Semi Quantitative Reverse Transcriptase (Rt)-pcrmentioning

confidence: 99%

“…It has been demonstrated that the expression of MMP-12 is markedly induced in the kidneys of anti-GBM nephritis mice and Alport mice [5,16]. However, the functions of MMP-12 in kidney diseases have not been completely elucidated.…”

mentioning

confidence: 99%

“…However, the functions of MMP-12 in kidney diseases have not been completely elucidated. In this study, we investigated the levels of MMP-12 and its regulatory molecules, monocyte chemoattractive protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) [16], in the kidneys of ICGN mice by Western blotting, semi-quantitative RT-PCR, and immunohistochemical staining, respectively. …”

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confidence: 99%

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Expression of Macrophage Metalloelastase (MMP-12) in Podocytes of Hereditary Nephrotic Mice (ICGN Strain)

Uchio

Sawada

Manabe

2009

The Journal of Veterinary Medical Science

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ABSTRACT. The Institute for Cancer Research (ICR)-derived glomerulonephritis (ICGN) mouse is a good model for renal fibrosis. In the glomeruli and tubulointerstitium of ICGN mouse kidneys, the components of the extracellular matrix (ECM) accumulated, and matrix metalloproteinases (MMPs) participated in this process. To clarify the mechanism of renal fibrosis, we investigated the expression and localization of macrophage metalloelastase (MMP-12), whose functions in kidney diseases are not fully understood, and its regulatory molecules, monocyte chemoattractive protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2), in the kidneys of ICGN mice by RT-PCR, Western blotting and immunohistochemical staining, respectively. Extensive expression of MMP-12 mRNA and its protein was noted in ICGN mice with progressed nephrotic syndrome. The increase in MMP-12 expression occurred predominantly in podocytes. Furthermore, MCP-1 and CCR2 were also increased in podocytes of the ICGN strain. These results suggest that the expression of MMP-12 is involved in the progression of nephrotic syndrome in ICGN mice. The Institute for Cancer Research (ICR)-derived glomerulonephritis (ICGN) mouse is an inbred strain with nephrotic syndrome. It is affected by heavy proteinuria, hypoalbuminemia, hypercholesterolemia, systemic edema and anemia. Histological studies show a thickened glomerular basement membrane (GBM) and effacement of podocyte foot processes at an early age [9][10][11][12][13][14]. We previously found that components of the extracellular matrix (ECM) accumulate in the glomeruli and tubulointerstitium of ICGN kidneys [2,3,19], and that the accumulation was due to hyper-production and less degradation of the ECM components [20,21,23]. We measured biochemically the activity and the expression level of matrix metalloproteinase (MMP)-2 and MMP-9 in ICGN kidneys, and found decreased levels in comparison with normal ICR mice [20]. However, the expression of MMP-2 and MMP-9 was observed at renal tubules but not glomeruli [23]. These results suggest that small amounts of MMP-2 and MMP-9 participate in the progression of tubulointerstitial fibrosis in ICGN mice, though the mechanisms of glomerular fibrosis have not been fully elucidated yet.MMP-12 has broad substrate specificity, recognizing elastin, collagen IV, laminins, entactin, and 1-antitrypsin, being associated with lung diseases, atherosclerosis, cancers, and skin diseases [4,6,7,18,24,26]. It has been demonstrated that the expression of MMP-12 is markedly induced in the kidneys of anti-GBM nephritis mice and Alport mice [5,16]. However, the functions of MMP-12 in kidney diseases have not been completely elucidated. In this study, we investigated the levels of MMP-12 and its regulatory molecules, monocyte chemoattractive protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) [16], in the kidneys of ICGN mice by Western blotting, semi-quantitative RT-PCR, and immunohistochemical staining, respectively. MATERIALS AND METHODSAnimals and tissue preparation: ICGN mice were classified in...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 50%

Section: Synthesis and Semi Quantitative Reverse Transcriptase (Rt)-pcrmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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