Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Experimental and Clinical Research Center, a joint cooperation between the Max Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany; Berlin Institute of Health, Berlin, Germany.
Kidney Int. 2019 Jan;95(1):108-122. doi: 10.1016/j.kint.2018.08.028. Epub 2018 Nov 15.
Bone morphogenetic protein (BMP) signaling has been shown to modulate the development of renal fibrosis in animal models of kidney injury, but the downstream mediators are incompletely understood. In wild-type mice, canonical BMP signaling mediated by SMAD1/5/8 transcription factors was constitutively active in healthy renal tubules, transiently down-regulated after ischemia reperfusion injury (IRI), and reactivated during successful tubular regeneration. We then induced IRI in mice with a tubular-specific BMP receptor 1A (BMPR1A) deletion. These mice failed to reactivate SMAD1/5/8 signaling in the post-ischemic phase and developed renal fibrosis after injury. Using unbiased genomic analyses, we identified three genes encoding inhibitor of DNA-binding (ID) proteins (Id1, Id2, and Id4) as key targets of BMPR1A-SMAD1/5/8 signaling. BMPR1A-deficient mice failed to re-induce these targets following IRI. Instead, BMPR1A-deficiency resulted in activation of pro-fibrotic signaling proteins that are normally repressed by ID proteins, namely, p38 mitogen-activated protein kinase and cell cycle inhibitor p27. These data indicate that the post-ischemic activation of canonical BMP signaling acts endogenously to repress pro-fibrotic signaling in tubular cells and may help to prevent the progression of acute kidney injury to chronic kidney disease.
骨形态发生蛋白（BMP）信号已被证明可调节动物肾损伤模型中的肾纤维化发育，但下游介质尚不完全清楚。在野生型小鼠中，健康肾小管中 SMAD1/5/8 转录因子介导的经典 BMP 信号持续活跃，缺血再灌注损伤（IRI）后短暂下调，并在成功的肾小管再生期间重新激活。然后，我们在具有肾小管特异性 BMP 受体 1A（BMPR1A）缺失的小鼠中诱导 IRI。这些小鼠在缺血后阶段未能重新激活 SMAD1/5/8 信号，并在损伤后发展为肾纤维化。使用无偏基因组分析，我们确定了三个编码 DNA 结合抑制剂（ID）蛋白（Id1、Id2 和 Id4）的基因作为 BMPR1A-SMAD1/5/8 信号的关键靶标。IRI 后 BMPR1A 缺陷型小鼠未能重新诱导这些靶标。相反，BMPR1A 缺陷导致通常受 ID 蛋白抑制的促纤维化信号蛋白的激活，即 p38 丝裂原活化蛋白激酶和细胞周期抑制剂 p27。这些数据表明，缺血后经典 BMP 信号的激活可内源性抑制肾小管细胞中的促纤维化信号，并可能有助于防止急性肾损伤进展为慢性肾脏病。
