Krämer Stephanie, Wang-Rosenke Yingrui, Scholl Valeska, Binder Eva, Loof Tanja, Khadzhynov Dmytro, Kawachi Hiroshi, Shimizu Fujio, Diekmann Fritz, Budde Klemens, Neumayer Hans-H, Peters Harm
Department of Nephrology and Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany.
Am J Physiol Renal Physiol. 2008 Feb;294(2):F440-9. doi: 10.1152/ajprenal.00379.2007. Epub 2007 Dec 19.
Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg.kg(-1).body wt(-1)) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. Kruskal-Wallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (-38%), systolic blood pressure (-16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (-61 and -24%), transforming growth factor-beta1 overexpression (-41 and -47%), collagen I deposition (-53 and -65%), cell proliferation (-90 and -76%), and leukocyte number (macrophages -52 and -53%; lymphocytes -58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine -0.68 mg/dl, urea -66.7 mg/day, and creatinine clearance +0.13 ml.min(-1).100 g body wt(-1)). In conclusion, low-dose mTOR inhibition by rapamycin limits the progressive course of anti-thy1-induced renal disease toward chronic glomerulosclerosis, tubulointerstitial fibrosis, and renal insufficiency. Renoprotection by rapamycin involved significant beneficial effects on multiple key pathways in the progression of chronic renal disease, i.e., proteinuria, extracellular matrix accumulation, renal cell proliferation, and inflammatory cell infiltration.
人类系膜增生性肾小球肾炎/硬化症（主要是IgA肾病）的治疗选择有限。进行性系膜增生性肾病是终末期肾病的主要原因。本研究探讨了雷帕霉素低剂量抑制mTOR在系膜增生性肾小球硬化症（cGS）慢性进展模型中的疗效。通过向单侧肾切除的大鼠注射高剂量抗thy1抗体诱导cGS。抗体注射10天后开始给予雷帕霉素（2.5mg·kg-1·体重-1），持续至第20周。cGS的特征是蛋白尿进展、血压升高、明显的肾小管间质和肾小球纤维化、细胞增殖和圆形细胞浸润以及肾功能受损。采用Kruskal-Wallis和Mann-Whitney U检验进行统计分析。低剂量雷帕霉素治疗可显著减轻慢性抗thy1诱导的肾小球硬化进程。在第20周时，蛋白尿（-38%）、收缩压（-16mmHg）、肾小管间质和肾小球组织学基质积累（-61%和-24%）、转化生长因子-β1过表达（-41%和-47%）、I型胶原沉积（-53%和-65%）、细胞增殖（-90%和-76%）以及白细胞数量（巨噬细胞-52%和-53%；淋巴细胞-58%和51%）的改善证明了这一点。雷帕霉素也改善了肾功能（血肌酐-0.68mg/dl、尿素-66.7mg/天、肌酐清除率+0.13ml·min-1·100g体重-1）。总之，雷帕霉素低剂量抑制mTOR可限制抗thy1诱导的肾脏疾病向慢性肾小球硬化、肾小管间质纤维化和肾功能不全的进展过程。雷帕霉素的肾脏保护作用涉及对慢性肾病进展中多个关键途径的显著有益影响，即蛋白尿、细胞外基质积累、肾细胞增殖和炎性细胞浸润。
