In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy

Abstract

Progressive expansion of the mesangial matrix is one of the most characteristic histological features of diabetic nephropathy (DN). To determine the balance between the turnover and degradation of extracellular matrix (ECM) in renal tissue of patients with DN, we examined the expression of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and type IV collagen (IV-C) mRNAs using a high-resolution in situ hybridization. Patients were divided into three grades: mild (grade I), moderate (grade II) and severe (grade III) mesangial expansion and tubulointerstitial injury. The relationship between the expression of these mRNAs and degree of glomerular mesangial expansion and interstitial injury was also examined. Cells positive for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman's capsule. A number of tubular epithelial cells and some infiltrating cells in the interstitium also expressed these mRNAs. The expression of MMP-3 mRNA and TIMP-1 mRNA was strongest in glomeruli of grade I and inversely correlated with mesangial expansion. In contrast, the expression of all three types of mRNA was correlated with the degree of interstitial injury. Our results indicate that IV-C, MMP-3 and TIMP-1 mRNAs are expressed in glomerular resident cells, tubular epithelial cells and infiltrating cells in renal tissue of DN, and suggest that their expression changes with the degree of mesangial expansion and interstitial injury. Altered expression of MMP-3 and TIMP-1 may be associated with the progression of DN.

DNA microarray analysis of the gene expression profile of kidney tissue in a type 2 diabetic rat model

“…Matrix metalloproteinase inhibitor gene 1 (Timp-1) was also found to be up-regulated in the kidney tissue of the T2D rats, consistent with a report by Suzuki et al (18), which showed that the expression of the Timp-1 gene was up-regulated in renal parenchymal and infiltrating cells in patients with ND. TIMP-1 is thought to play a role in resistance to lymphocyte-mediated apoptosis in vivo by decreasing the activity of NF-κB (19).…”

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

“…Although induction of MMP-3 and MMP-9 are well documented in glomerular disease, 31,32 expression of MMP-12 in normal or diseased glomeruli has not been documented, with the exception of autoimmune glomerulonephritis, where the MMP-12 expression is due to infiltrating macrophages. 18 Kidneys from wild-type and 7-week-old Alport mice were immunostained using antibodies specific for MMP-12.…”

Increases in Renal ε-(γ-Glutamyl)-Lysine Crosslinks Result from Compartment-Specific Changes in Tissue Transglutaminase in Early Experimental Diabetic Nephropathy: Pathologic Implications

“…In particular, the mechanism underlying the expansion of the mesangial matrix remains poorly defined. Although some observations have suggested increased ECM synthesis to be the major cause, this was not universally found (Fukui et al, 1992;Suzuki et al, 1997). It has been suggested that there are qualitative changes in the ECM leading to alterations in the glomerular basement membrane (GBM) proteoglycan content, thus affecting the GBM charge (Wayl et al, 1982).…”