Down-regulation of glomerular matrix metalloproteinase-2 gene in human NIDDM

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.