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Expression and regulation of discoidin domain receptor 1 (DDR1) – a novel receptor for collagen – in normal human renal cells and patients with lupus nephritis
Arthritis Res Ther volume 5, Article number: 95 (2003)
Background and objective
Pathogenic accumulation of extracellular matrix (ECM) is a common feature of progressive renal diseases. Cytokines such as TGF-β as well as aberrant communication of renal cells with ECM via specific cell-surface receptors are thought to play a pivotal role in this process. Recently, a novel receptor tyrosine kinase subfamily has been identified and designated as discoidin domain receptor tyrosine kinase type 1 (DDR1) and type 2 (DDR2). These are functional collagen receptors, whose tyrosine kinase is activated upon binding to collagen. We sought to explore the expression and regulation of DDR1 in the human kidney in both normal and diseased states.
We used cultured human mesangial and tubular cells and renal biopsies from patients with lupus nephritis or normal kidneys obtained from nephrectomies. DDR1 expression was studied by immunohistochemistry and Northern and Western blot analyses. Tyrosine phosphorylation was detected by immunoblotting using antiphosphotyrosine blots.
High levels of DDR1 expression were detected by immunohistochemistry in glomerular epithelial and mesangial cells (MCs) of normal human kidney specimens. DDR1 was also expressed in renal tubular epithelial cells, albeit at lower levels. As compared with normal controls, DDR1 expression was significantly decreased in mesangial areas obtained from patients with proliferative lupus nephritis (n = 7), while it was up-regulated in tubular epithelial cells surrounded by significant interstitial fibrosis. Cultured human MCs expressed DDR1 in vitro, a finding verified by Western and Northern blot analysis. Stimulation of MCs with collagen induced tyrosine phosphorylation of DDR1, indicating that mesangial DDR1 is a functional collagen receptor. Interestingly, platelet-derived growth factor and basic fibroblast growth factor, both of which are potent mitogens for MCs, significantly decreased the expression of DDR1 both in mRNA and protein levels. TGF-β did not exert such an effect.
DDR1 participates in the interaction of MCs with mesangial ECM. Decreased expression of DDR1 in MCs may represent an important process for mesangial proliferation.
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Boumpas, D., Kuroiwa, T. Expression and regulation of discoidin domain receptor 1 (DDR1) – a novel receptor for collagen – in normal human renal cells and patients with lupus nephritis. Arthritis Res Ther 5, 95 (2003) doi:10.1186/ar725
- Lupus Nephritis
- Tubular Epithelial Cell
- Renal Tubular Epithelial Cell
- Progressive Renal Disease