Altered Expression of Matrix-Related Molecules in the Development of Chronic Thy1.1 Nephritis

Abstract

Background/Aim: Matrix production and degradation are critically important in chronic nephritis. Our aim was to investigate the precise expression of matrix-related molecules which is essential for understanding the pathogenesis of renal disease. Methods: Chronic nephritis was induced by a single injection of anti-Thy1.1 antibody to unilaterally nephrectomized rats. RNA was extracted from renal cortex and isolated glomeruli 4, 7, and 10 weeks after the antibody injection. Matrix-related gene expressions were measured by polymerase chain reaction. The expression of α1(IV) and α3(IV) collagens was studied by immunohistochemistry. The gelatinolytic activity in the glomeruli was assayed by gelatin zymography. Results: Polymerase chain reaction revealed an increase of α1(IV) in both glomeruli and renal cortex from nephritic rats. In contrast, the expression of α3(IV), normally a component of the glomerular basement membrane, was decreased in nephritic animals. Immunohistochemistry confirmed the finding that α1(IV) and α3(IV) were up- and downregulated, respectively, in the glomeruli. Gene expression and activity of matrix metalloproteinase 2 were enhanced, while those of matrix metalloproteinase 9 were clearly suppressed in nephritis. Conclusions: Downregulation of α3(IV) and enhancement of the matrix metalloproteinase-2 activity in the glomeruli may contribute to the glomerular damage by altering the glomerular basement membrane components. Impairment of the glomerular basement membrane integrity may possibly be implicated in irreversible renal dysfunction.

Renoprotective Action of a Matrix Metalloproteinase Inhibitor in Progressive Mesangioproliferative Nephritis

“…Therefore, damage of the GBM and GECs leads to an increase in proteinuria. We have previously reported sustained proteinuria in chronic anti-Thy1.1 nephritic rats, associated with a decreased number of ACSs on the GBM, an abnormal remodeling of type IV collagen in the GBM, and predominant injury in GECs [16,27]. The present study demonstrates that the treatment with the MMP inhibitor compound A prevented the loss of ACSs on the GBM.…”

“…It has been reported that MMP−2 contributes to the process of phenotype changes in MCs and TECs [10,11,15]. We have previously demonstrated that MMP−2 activity is enhanced in anti-Thy1.1 nephritis [16]. Compound A obviously suppressed ECM deposition with decreased gene expressions of TGF-β1 as well as α1(I), α1(III), and α1(IV) collagen in the renal cortex.…”

“…These results show that the renoprotective effect of compound A on nephritis is associated with a relief of the deterioration in GBM constitution and function and conservation of GEC function. We have previously discussed that MMP−2 causes extensive structural remodeling during glomerular injury due to its possible involvement in the disruption of the GBM [16]. An abnormal structure of the GBM may rupture the contact with GECs, leading to GEC disorder.…”

“…After injury, increased activity of MMP−2, which is secreted by mesangial cells (MCs) in glomeruli and leukocytes penetrating into the glomerular basement membrane (GBM), results in the degradation of the GBM [13,14,15]. We have previously shown that upregulation of MMP−2 in glomeruli contributes to glomerular damage by altering the GBM component in nephritic rats [16]. Furthermore, in patients with CKD, increased MMP−2 expression in glomeruli and a significant correlation between circulating MMP−2 activity and serum creatinine concentration have been reported [17,18].…”