Seattle Children's Hospital Research Institute, University of Washington, Seattle, Washington;
J Am Soc Nephrol. 2014 Jan;25(1):43-54. doi: 10.1681/ASN.2012090962. Epub 2013 Sep 5.
Therapy to slow the relentless expansion of interstitial extracellular matrix that leads to renal functional decline in patients with CKD is currently lacking. Because chronic kidney injury increases tissue oxidative stress, we evaluated the antifibrotic efficacy of cysteamine bitartrate, an antioxidant therapy for patients with nephropathic cystinosis, in a mouse model of unilateral ureteral obstruction. Fresh cysteamine (600 mg/kg) was added to drinking water daily beginning on the day of surgery, and outcomes were assessed on days 7, 14, and 21 after surgery. Plasma cysteamine levels showed diurnal variation, with peak levels similar to those observed in patients with cystinosis. In cysteamine-treated mice, fibrosis severity decreased significantly at 14 and 21 days after unilateral ureteral obstruction, and renal oxidized protein levels decreased at each time point, suggesting reduced oxidative stress. Consistent with these results, treatment of cultured macrophages with cysteamine reduced cellular generation of reactive oxygen species. Furthermore, treatment with cysteamine reduced α-smooth muscle actin-positive interstitial myofibroblast proliferation and mRNA levels of extracellular matrix proteins in mice and attenuated myofibroblast differentiation and proliferation in vitro, but did not augment TGF-β signaling. In a study of renal ischemia reperfusion, cysteamine therapy initiated 10 days after injury and continued for 14 days decreased renal fibrosis by 40%. Taken together, these data suggest previously unrecognized antifibrotic actions of cysteamine via TGF-β-independent mechanisms that include oxidative stress reduction and attenuation of the myofibroblast response to kidney injury and support further investigation into the potential benefit of cysteamine therapy in the treatment of CKD.
目前缺乏治疗慢性肾脏病患者间质细胞外基质不断扩张导致肾功能下降的方法。由于慢性肾损伤会增加组织氧化应激，我们评估了半胱胺酒石酸盐（一种治疗胱氨酸病肾病的抗氧化疗法）在单侧输尿管梗阻小鼠模型中的抗纤维化疗效。手术当天开始，将新鲜半胱胺（600mg/kg）添加到饮用水中，每天一次，并在手术后第 7、14 和 21 天评估结果。血浆半胱胺水平呈昼夜变化，峰值水平与胱氨酸病患者观察到的水平相似。在半胱胺治疗的小鼠中，单侧输尿管梗阻后 14 天和 21 天纤维化严重程度显著降低，肾脏氧化蛋白水平在每个时间点均降低，表明氧化应激减少。与这些结果一致的是，用半胱胺处理培养的巨噬细胞可减少细胞产生的活性氧。此外，半胱胺治疗可减少小鼠的α-平滑肌肌动蛋白阳性间质肌成纤维细胞增殖和细胞外基质蛋白的 mRNA 水平，并减弱体外肌成纤维细胞的分化和增殖，但不会增强 TGF-β信号。在肾缺血再灌注研究中，损伤后 10 天开始并持续 14 天的半胱胺治疗可使肾脏纤维化减少 40%。总之，这些数据表明半胱胺具有以前未被认识到的抗纤维化作用，其机制与 TGF-β无关，包括减少氧化应激和减弱肌成纤维细胞对肾脏损伤的反应，并支持进一步研究半胱胺治疗在慢性肾脏病治疗中的潜在益处。
