Objective: Enhanced expression of transforming growth factor-beta (TGF-β) in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end-organ damage. Disintegrin and metalloproteinases 9 (ADAM9) activate TGF-β1 by cleaving the latency-associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGF-β1.
Methods: We assessed the expression of ADAM9 in the kidneys of lupus-prone mice and humans. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the upregulation of ADAM9 and the subsequent activation of TGF-β1. To assess the role of ADAM9 in the development of tubular-intestinal fibrosis in LN, we generated MRL/lpr. Adam9-deficient mice.
Results: ADAM9 was highly expressed in tubules from MRL/lpr. mice. The transcription factor hypoxia-inducible factor-1 alpha was found to promote the transcription of ADAM9 in TECs. TECs from Adam9-deficient mice exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGF-β1 from latent TGF-β1. Co-culture of TECs from Adam9-deficient mice with fibroblasts in the presence of dimethyloxalylglycine and latent TGF-β1 produced decreased amounts of type I collagen and alpha-smooth muscle actin (α-SMA) by fibroblasts. Adam9-deficient MRL/lpr mice showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found increased.
Conclusion: Hypoxia promotes the expression of ADAM9 by TECs which is responsible for the development of interstitial fibrosis in LN by enhancing the TGF-β1 activation which promotes fibroblasts to produce collagen and α-SMA.
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