Date: Sunday, November 7, 2021
Session Title: Abstracts: SLE – Etiology & Pathogenesis (0970–0973)
Session Type: Abstract Session
Session Time: 2:30PM-2:45PM
Background/Purpose: 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 (J Immunol. 180, 1903-1912. 2008). We previously reported that a disintegrin and metalloproteinases 9 (ADAM9) enhances Th17 cell differentiation and autoimmunity by activating TGF-β1 (PNAS. 118, 2021). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGF-β1.
Methods: We assessed the expression of ADAM9 in kidneys from MRL/lpr mice and control MPJ mice and determined the expression levels of ADAM9 in kidney cells. We conducted in vitro experiments using tubular epithelial cells (TEC) isolated from B6 mice and explored the mechanisms responsible for the upregulation of ADAM9 in tubular epithelial cells (TEC) and the subsequent activation of TGF-β1 by ADAM9 expressed in TEC. To assess the role of ADAM9 in the development of tubular-intestinal fibrosis in LN, we generated MRL/lpr.Adam9-/- mice and compared the intensity of renal fibrosis between Adam9 sufficient and deficient MRL/lpr mice.
Results: We identified ADAM9 to be highly expressed in tubules from MRL/lpr mice. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) was found to promote the transcription of ADAM9 in TEC. TEC from Adam9-deficient mice exposed to the hypoxia inducer dimethyloxalylglycine (DMOG) failed to cleave the latency-associated peptide to produce bioactive TGF-β1 from latent TGF-β1. Co-culture of TEC from Adam9-deficient mice and fibroblasts with DMOG and latent TGF-β1 showed decreased production of type I collagen and alpha-smooth muscle actin (αSMA) by fibroblasts. Adam9-deficient MRL/lpr mice showed mitigated tubular-intestinal fibrosis.
Conclusion: Our findings have revealed that hypoxia promotes the expression of ADAM9 by TEC which is responsible for the development of interstitial fibrosis in LN by promoting the generation of fibroblast bioactive TGF-β1 [hypoxia (HIF-1α) -> ADAM9 -> TGF-β1 -> production of collagen I and αSMA by resident fibroblasts].
To cite this abstract in AMA style:Umeda M, Satyam A, Yoshida N, Bhargava R, Hisada R, Jamaly S, Owen C, Tsokos G. Hypoxia Promotes the Expression of ADAM9 by Tubular Epithelial Cells Which Enhances TGF-β1 Activation and Promotes Tissue Fibrosis in Lupus Nephritis [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 10). https://acrabstracts.org/abstract/hypoxia-promotes-the-expression-of-adam9-by-tubular-epithelial-cells-which-enhances-tgf-%ce%b21-activation-and-promotes-tissue-fibrosis-in-lupus-nephritis/. Accessed January 22, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hypoxia-promotes-the-expression-of-adam9-by-tubular-epithelial-cells-which-enhances-tgf-%ce%b21-activation-and-promotes-tissue-fibrosis-in-lupus-nephritis/