Canonical BMP signaling in tubular cells mediates recovery after acute kidney injury.
Canonical BMP signaling in tubular cells mediates recovery after acute kidney injury.
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DOI：
10.1016/j.kint.2018.08.028
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发表时间：
2019-01
影响因子：
19.6
通讯作者：
E. Vigolo;L. Markó;C. Hinze;D. Müller;R. Schmidt-Ullrich;K. Schmidt-Ott
中科院分区：
文献类型：
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作者：
E. Vigolo;L. Markó;C. Hinze;D. Müller;R. Schmidt-Ullrich;K. Schmidt-Ott
骨形态发生蛋白（BMP）信号转导已被证明可以调节肾损伤动物模型中肾纤维化的发展，但下游介质尚未完全了解。在野生型小鼠中，SMAD 1/5/8转录因子介导的典型BMP信号传导在健康肾小管中组成性活跃，在缺血再灌注损伤（IRI）后短暂下调，并在成功的肾小管再生过程中重新激活。然后，我们诱导IRI的小鼠与肾小管特异性BMP受体1A（BMPR 1A）删除。这些小鼠在缺血后阶段未能重新激活SMAD 1/5/8信号传导，并在损伤后发生肾纤维化。使用无偏基因组分析，我们确定了三个基因编码的DNA结合（ID）蛋白（Id 1，Id 2和Id 4）的抑制剂作为BMPR 1A-SMAD 1/5/8信号转导的关键目标。BMPR 1A缺陷小鼠在IRI后未能重新诱导这些靶点。相反，BMPR 1A缺陷导致通常被ID蛋白抑制的促纤维化信号蛋白的激活，即p38促分裂原活化蛋白激酶和细胞周期抑制剂p27。这些数据表明，典型BMP信号传导的缺血后激活内源性地抑制肾小管细胞中的促纤维化信号传导，并且可能有助于防止急性肾损伤进展为慢性肾病。
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.