Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.
J Am Soc Nephrol. 2013 Feb;24(2):229-42. doi: 10.1681/ASN.2012070678. Epub 2012 Dec 20.
The signals that drive fibrogenesis after an initiating insult to the kidney are incompletely understood. Here, we report that renal nerve stimulation after ureteral obstruction is the primary profibrotic signal and that renal denervation prevents both fibrogenesis and the inflammatory cascade. Local infusion of neural factors, norepinephrine, and calcitonin gene-related peptide (CGRP) in denervated kidneys mimicked the fibrotic response observed in innervated obstructed kidneys. Norepinephrine and CGRP act through the α(2)-adrenergic receptor and CGRP receptor, respectively, because blocking these receptors prevented fibrosis, the inflammatory response, and tubular cell death. In tubular epithelial cells, both norepinephrine and CGRP induced apoptosis and the release of profibrotic factors capable of stimulating the differentiation of fibroblasts to myofibroblasts. In conclusion, these data suggest that nerve-derived signaling molecules may drive renal fibrosis and that their suppression may be a therapeutic approach to fibrosis prevention.
肾脏受到初始损伤后导致纤维化的信号尚未完全阐明。本文报告称，输尿管梗阻后肾脏神经刺激是主要的致纤维化信号，而肾脏去神经支配可预防纤维化和炎症级联反应。去神经支配肾脏中局部输注神经因子、去甲肾上腺素和降钙素基因相关肽（CGRP）可模拟未受神经支配的梗阻肾脏中观察到的纤维化反应。去甲肾上腺素和 CGRP 通过α(2)-肾上腺素能受体和 CGRP 受体起作用，因为阻断这些受体可预防纤维化、炎症反应和肾小管细胞死亡。在肾小管上皮细胞中，去甲肾上腺素和 CGRP 均可诱导细胞凋亡和释放能够刺激成纤维细胞向肌成纤维细胞分化的促纤维化因子。总之，这些数据表明，神经来源的信号分子可能驱动肾脏纤维化，抑制这些信号分子可能是预防纤维化的一种治疗方法。
