Regulation of Fibrillin-1 by Biglycan and Decorin Is Important for Tissue Preservation in the Kidney During Pressure-Induced Injury

Abstract

There is growing evidence that the two small leucinerich proteoglycans biglycan and decorin regulate the assembly of connective tissues and alter cell behavior during development and pathological processes. In this study, we have used an experimental animal model of unilateral ureteral ligation and mice deficient in either biglycan or decorin. We discovered that pressure-induced injury to the wild-type kidneys led to overexpression of decorin, biglycan, fibrillin-1, and fibrillin-2. In contrast, in biglycan-deficient kidneys the overexpression of fibrillin-1 was markedly attenuated and this was associated with cystic dilatation of Bowman's capsule and proximal tubules. Notably, we found that in ligated kidneys from decorin-null mice, fibrillin-1 expression was initially enhanced to the same extent as in wild-type animals. However, long-term obstruction resulted in down-regulation of fibrillin-1 and concurrent cystic dilatation of Bowman's capsule in 33% of kidneys at 5 months after obstruction. In all of the genotypes, no differences in fibrillin-2 expression were observed. These in vivo data correlated with a significant induction of fibrillin-1 expression in renal fibroblasts and mesangial cells by recombinant biglycan and decorin. Biglycan and decorin belong to the family of small leucine-rich proteoglycans (SLRPs), which are characterized by core proteins with centrally located leucine-rich motifs flanked by cysteine clusters and by one (decorin) or two (biglycan) chondroitin/dermatan-sulfate side chains. SLRPs are primarily considered to play a role in collagen fibril formation and stability.

Renal Accumulation of Biglycan and Lipid Retention Accelerates Diabetic Nephropathy

“…21,22 The differences between our study and previous studies could simply be due to differences in the antibody affinity or to the examination of different stages of renal disease. In addition, the functional role or roles of biglycan are unclear; roles have been proposed in the maintenance of the glomerular charge barrier, 48,49 in the regulation of mesangial cell growth and survival, 50 in the regulation of TGF-␤ activity, 51 in the regulation of inflammation via activation of Toll-like receptors, 52 in the regulation of the assembly of connective tissues, 53 and in the structural composition of fibrosis, 22 among others. Both biglycan and decorin can bind TGF-␤, leading to its sequestration and neutralization of activity.…”

Enhanced fibrillin-2 expression is a general feature of wound healing and sclerosis: potential alteration of cell attachment and storage of TGF-β

“…39,40 (ii) In pressure-induced kidney fibrosis, an increase of fibrillin-2 expression was shown by immunohistochemistry and western blotting. 41 (iii) In a wound-healing study, using an antibody against both fibrillin isoforms, fibrillin was identified in the wound tissue. 42 Fibroblasts in normal skin are thought to be in a quiescent state characterized by a low synthesis of extracellular matrix components.…”

Co-expression of FBN1 with mesenchyme-specific genes in mouse cell lines: implications for phenotypic variability in Marfan syndrome

“…Biglycan protein (encoded by Bgn) has been reported to stimulate synthesis of fibrillin-1 in pressure-induced renal injury and may have a more general role in assembly of connective tissue. 36 No disease has been associated with BGN mutation in humans but Bgn-deficient mice have a skeletal phenotype. 37 Lysyl oxidase (Lox gene) may be important in overall assembly of elastic microfibrils (reviewed in Wagenseil and Mecham 38 ) and may be involved in preparing tumour cells for metastasis.…”