Umeda Masataka, Karino Kohei, Satyam Abhigyan, Yoshida Nobuya, Hisada Ryo, Bhargava Rhea, Vichos Theodoros, Kunzler Ana Laura, Igawa Takashi, Ichinose Kunihiro, Torigoe Kenta, Nishino Tomoya, Maeda Takahiro, Owen Caroline A, Abdi Reza, Kawakami Atsushi, Tsokos George C
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, and Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Arthritis Rheumatol. 2025 Feb;77(2):180-189. doi: 10.1002/art.42987. Epub 2024 Oct 1.
Enhanced expression of transforming growth factor (TGF) β in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end-organ damage. ADAM9 activates TGFβ1 by cleaving the latency-associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGFβ1.
We assessed the expression of ADAM9 in the kidneys of mice and humans who were lupus prone. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the up-regulation of ADAM9 and the subsequent activation of TGFβ1. To assess the role of ADAM9 in the development of tubular-intestinal fibrosis in individuals with LN, we generated MRL/lpr mice who were Adam9 deficient.
ADAM9 was highly expressed in tubules from MRL/lpr mice. The transcription factor hypoxia-inducible factor-1α was found to promote the transcription of ADAM9 in TECs. TECs from mice who were Adam9 deficient and exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGFβ1 from latent TGFβ1. Coculture of TECs from mice who were Adam9 deficient with fibroblasts in the presence of dimethyloxalylglycine and latent TGFβ1 produced decreased amounts of type I collagen and α-smooth muscle actin (SMA) by fibroblasts. MRL/lpr mice who were Adam9 deficient showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found to increase.
Hypoxia promotes the expression of ADAM9 by TECs, which is responsible for the development of interstitial fibrosis in patients with LN by enhancing the TGFβ1 activation, which promotes fibroblasts to produce collagen and α-SMA.
狼疮性肾炎（LN）患者肾脏中转化生长因子（TGF）β表达增强可导致进行性纤维化，进而造成终末器官损害。ADAM9通过切割潜伏相关肽（LAP）激活TGFβ1。我们推测肾脏中的ADAM9可能通过激活TGFβ1加速纤维化形成。
我们评估了狼疮易感小鼠和人类肾脏中ADAM9的表达。使用从小鼠分离的肾小管上皮细胞（TECs）进行体外实验，探究ADAM9上调及随后TGFβ1激活的机制。为评估ADAM9在LN患者肾小管间质纤维化发展中的作用，我们构建了Adam9基因缺陷的MRL/lpr小鼠。
ADAM9在MRL/lpr小鼠的肾小管中高表达。发现转录因子缺氧诱导因子-1α可促进TECs中ADAM9的转录。Adam9基因缺陷且暴露于缺氧模拟剂二甲基草酰甘氨酸的小鼠的TECs无法切割LAP以从潜伏性TGFβ1产生生物活性TGFβ1。在二甲基草酰甘氨酸和潜伏性TGFβ1存在的情况下，将Adam9基因缺陷小鼠的TECs与成纤维细胞共培养，成纤维细胞产生的I型胶原蛋白和α平滑肌肌动蛋白（SMA）量减少。Adam9基因缺陷的MRL/lpr小鼠的间质纤维化减轻。在转化水平上，发现LN患者组织和尿液中ADAM9表达增加。
缺氧促进TECs表达ADAM9，后者通过增强TGFβ1激活导致LN患者间质纤维化发展，而TGFβ1激活促进成纤维细胞产生胶原蛋白和α-SMA。
