Abstract：
In infantile nephropathic cystinosis, variants of the CTNS gene cause accumulation of cystine in lysosomes, causing progressive damage to most organs. Patients usually present before 1 year of age with signs of renal Fanconi syndrome. Cysteamine therapy allows cystine clearance from lysosomes and delays kidney damage but does not prevent progression to end-stage kidney disease, suggesting that pathways unrelated to cystine accumulation are also involved. Among these, impaired autophagy, altered endolysosomal trafficking, and increased apoptosis have emerged in recent years as potential targets for new therapies. We previously showed that luteolin, a flavonoid compound, improves these abnormal pathways in cystinotic cells and in zebrafish models of the disease. Herein, we have investigated if prolonged luteolin treatment ameliorates kidney damage in a murine model of cystinosis. To this end, we have treated Ctns-/- mice from 2 to 8 months with 150 mg/kg/day of luteolin. No significant side effects were observed. Compared to untreated animals, analyses of kidney cortex samples obtained after sacrifice showed that luteolin decreased p62/SQSTM1 levels (p <0.001), improved the number, size, and distribution of LAMP1-positive structures (p <0.02), and decreased tissue expression of cleaved caspase 3 (p <0.001). However, we did not observe improvements in renal Fanconi syndrome and kidney inflammation. Kidney function remained normal during the time of the study. These results indicate that luteolin has positive effects on the apoptosis and endo-lysosomal defects of cystinotic proximal tubular cells. However, these beneficial effects did not translate into improvement of renal Fanconi syndrome.
摘要：
在婴儿肾病性膀胱炎中，CTNS基因的变异导致胱氨酸在溶酶体中积累，对大多数器官造成进行性损害。患者通常在1岁之前出现肾性Fanconi综合征的体征。半胱胺治疗允许从溶酶体中清除胱氨酸，延缓肾脏损害，但不能阻止进展为终末期肾脏疾病。这表明与胱氨酸积累无关的途径也参与其中。其中,自噬受损，改变内溶酶体运输，近年来，细胞凋亡增加已成为新疗法的潜在靶标。我们之前证明了木犀草素，黄酮类化合物，改善了囊肿细胞和斑马鱼疾病模型中的这些异常途径。在这里，我们已经研究了延长木犀草素治疗是否能改善鼠膀胱病模型的肾损伤。为此,我们用150mg/kg/天的木犀草素治疗了2至8个月的Ctns-/-小鼠。没有观察到明显的副作用。与未经治疗的动物相比，处死后获得的肾皮质样本分析显示木犀草素降低p62/SQSTM1水平（p<0.001），改进了数量,尺寸,和LAMP1-阳性结构的分布（p<0.02），并降低了裂解的caspase3的组织表达（p<0.001）。然而,我们未观察到肾性Fanconi综合征和肾脏炎症的改善.肾功能在研究期间保持正常。这些结果表明，木犀草素对囊性近端肾小管细胞的凋亡和内溶酶体缺陷具有积极作用。然而,这些有益作用并未转化为肾性Fanconi综合征的改善.
