Podocyte and endothelial-specific elimination of BAMBI identifies differential transforming growth factor-β pathways contributing to diabetic glomerulopathy
Podocyte and endothelial-specific elimination of BAMBI identifies differential transforming growth factor-β pathways contributing to diabetic glomerulopathy
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DOI：
10.1016/j.kint.2020.03.036
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发表时间：
2020-09-01
影响因子：
19.6
通讯作者：
Lee, Kyung
中科院分区：
文献类型：
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作者：
Lai, Han;Chen, Anqun;Lee, Kyung
转化生长因子-α（TGF-β）是糖尿病肾病的中心介质。由I型TGF-β受体ALK 5介导的TGF-β的作用和随后的Smad 2/3活化导致足细胞凋亡和损失。以前，我们证明了BMP和激活素膜结合抑制剂（BAMBI）（一种负调节剂TGF-β信号传导）的基因缺失会加速小鼠的糖尿病肾病。这与肾小球内皮细胞（EC）中ALK 1介导的Smad 1/5活化增强有关。因此，为了评估TGF-β在糖尿病肾病中的肾小球细胞特异性作用，我们检测了Bambi（Pod-Bambi-/-或EC-Bambi-/-）在链脲佐菌素诱导的糖尿病小鼠中的足细胞或EC特异性损失的作用。有趣的是，尽管高血糖症和体重减轻在所有糖尿病小鼠组中相似，但仅在糖尿病EC-Bambi-/-小鼠中存在显著的高血压。虽然BAMBI的足细胞或EC特异性损失都加速了糖尿病肾病的进展，但在糖尿病PodBambi-/-小鼠中观察到的足细胞损伤和损失恶化与Smad 3活化增强有关。增加Smad 1/5激活和EC增殖仅在糖尿病EC-Bambi-/-小鼠的肾小球中明显。糖尿病EC-Bambi-/-小鼠中Smad 1/5活化增强与肾小球质膜囊泡相关蛋白表达增加相关，表明未成熟或去分化的肾小球EC参与糖尿病肾病。值得注意的是，糖尿病EC-Bambi-/-小鼠显示足细胞损伤和损失与糖尿病Pod-Bambi-/-小鼠相当。因此，我们的研究结果突出了TGF-β信号传导的肾小球细胞特异性贡献和糖尿病肾病进展中受损肾小球细胞之间复杂的串扰。
Transforming growth factor-alpha (TGF-beta) is a central mediator of diabetic nephropathy. The effect of TGF-beta, mediated by the type I TGF-beta receptor, ALK5, and subsequent Smad2/3 activation results in podocyte apoptosis and loss. Previously, we demonstrated that the genetic deletion of the BMP and Activin Membrane-Bound Inhibitor (BAMBI), a negative modulator TGF-beta signaling, accelerates diabetic nephropathy in mice. This was associated with heightened ALK1-mediated activation of Smad1/5 in the glomerular endothelial cells (ECs). Therefore, to evaluate the glomerular cell-specific effects of TGF-beta in diabetic nephropathy we examined the effects of the podocyte- or EC-specific loss of Bambi (Pod-Bambi-/- or EC-Bambi-/-) in streptozotocin-induced diabetic mice with endothelial nitric oxide synthase deficiency. Interestingly, although hyperglycemia and body weight loss were similar in all groups of diabetic mice, significant hypertension was present only in the diabetic EC-Bambi-/- mice. While the podocyte or EC-specific loss of BAMBI both accelerated the progression of diabetic nephropathy, the worsened podocyte injury and loss observed in the diabetic PodBambi-/- mice were associated with enhanced Smad3 activation. Increased Smad1/5 activation and EC proliferation were apparent only in the glomeruli of diabetic EC-Bambi-/- mice. The enhanced Smad1/5 activation in diabetic EC-Bambi-/- mice was associated with increased glomerular expression of plasmalemma vesicle-associated protein, pointing to the involvement of immature or dedifferentiated glomerular ECs in diabetic nephropathy. Notably, diabetic EC-Bambi-/- mice displayed podocyte injury and loss that were comparable to diabetic Pod-Bambi-/- mice. Thus, our results highlight the glomerular cell-specific contribution of TGF-beta signaling and the intricate cross-talk between injured glomerular cells in the progression of diabetic nephropathy.