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Down-regulation of glomerular matrix metalloproteinase-2 gene in human NIDDM
D Del Prete1, F Anglani, M Forino
1Institute of Internal Medicine, University of Padova, Italy.
Abstract:
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.
Insights
In diabetic nephropathy, the MMP2 gene is down-regulated in glomeruli, unlike TIMP2. This MMP2 gene down-regulation is specific to diabetes and not a marker of kidney damage severity.
Area of Science:
- Nephrology
- Molecular Biology
- Diabetology
Background:
- Mesangial matrix deposition regulation involves synthesis and degradation.
- Matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) are key in matrix degradation.
- Diabetic nephropathy is associated with inhibited mesangial matrix degradation.
Purpose of the Study:
- To investigate the gene expression of MMP2 and TIMP2 in human diabetic nephropathy.
- To determine if MMP2 gene down-regulation is a marker of diabetic nephropathy progression.
Main Methods:
- Reverse transcription polymerase chain reaction (RT-PCR) on microdissected glomeruli and tubulo-interstitium.
- Analysis of kidney biopsies from 16 NIDDM patients, 5 other kidney disease patients, and 5 controls.
- Correlation with albumin excretion rate and renal histology in NIDDM patients.
Main Results:
- TIMP2 was expressed in both glomeruli and tubulo-interstitium across all groups.
- MMP2 gene was significantly down-regulated in glomeruli of all NIDDM patients.
- MMP2 gene expression was present in control and other kidney disease groups, but not in NIDDM glomeruli.
- MMP2 down-regulation was independent of albuminuria and renal histology in NIDDM patients.
Conclusions:
- MMP2 gene is consistently down-regulated in the glomeruli of NIDDM patients.
- The MMP2/TIMP2 expression pattern is distinctive in NIDDM.
- MMP2 gene down-regulation appears to be a consequence of diabetes itself, not a specific marker for nephropathy severity.