Matrilysin (MMP-7) Inhibition of BMP-7 Induced Renal Tubular Branching Morphogenesis Suggests a Role in the Pathogenesis of Human Renal Dysplasia

Abstract

SummaryCongenital renal dysplasia (RD) is a severe form of congenital renal malformation characterized by disruption of normal renal development with cyst formation, reduced or absent nephrons, and impaired renal growth. The authors previously identified that matrilysin (matrix metalloproteinase-7) was overexpressed in a microarray gene expression analysis of human RD compared to normal control kidneys. They now find that active matrilysin gene transcription and protein synthesis occur within dysplastic tubules and epithelial cells lining cysts in human RD by RT-PCR and immunohistochemistry. Similar staining patterns were seen in obstructed kidneys of pouch opossums that show histological features similar to that of human RD. In vitro, matrilysin inhibits formation of branching structures in mIMCD-3 cells stimulated by bone morphogenetic protein-7 (BMP-7) but does not inhibit hepatocyte growth factor-stimulated branching. BMP-7 signaling is essential for normal kidney development, and overexpression of catalytically active matrilysin in human embryonic kidney 293 cells reduces endogenous BMP-7 protein levels and inhibits phosphorylation of BMP-7 SMAD signaling intermediates. These findings suggest that matrilysin expression in RD may be an injury response that disrupts normal nephrogenesis by impairing BMP-7 signaling. (J Histochem Cytochem 60:243-253, 2012)

Association between urinary biomarkers MMP-7/TIMP-2 and reduced renal function in children with ureteropelvic junction obstruction

“…Encouragingly, the components of the model correlated well with existing knowledge of these urine biomarkers. Increased mRNA tissue expression of MMP-7 has been observed in embryological development of congenital renal dysplasia [ 21 , 22 ], chronic renal allograft rejection [ 23 , 24 ], as well as drug-induced nephropathy and obstructive uropathy via increased Wnt-beta catenin activity [ 25 ]. In our study, TIMP-2 levels were lower in UPJO patients with reduced renal function.…”

Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone

“…2 b) [ 30 ]. This process requires tissue transglutaminases (TGases), matrix metalloproteinases (MMPs) and membrane targeted MMPs (MT-MMPs) controlling synthesis, and degradation of extracellular matrix [ 31 , 32 ]. An equilibrated activity of those TGases directs also growth factor-stimulated signaling and in turn cell proliferation [ 33 , 34 ].…”

Matrilysin (MMP-7) catalytic activity regulates β-catenin localization and signaling activation in lung epithelial cells

“…The auto-activating matrilysin construct contains a furin cleavage site (RRKKR) inserted at the junction between the pro-and catalytic domains of the full-length human pro-matrilysin gene as previously described [15]. The catalytically inactive construct contains the furin cleavage site between the pro-and inactive-catalytic domains but with the addition of an amino acid substitution in the zinc-binding site of pro-matrilysin that prevents activation.…”