Hijmans Ryanne S, Rasmussen Daniel Guldager Kring, Yazdani Saleh, Navis Gerjan, van Goor Harry, Karsdal Morten Asser, Genovese Federica, van den Born Jacob
Division of Nephrology, Department of Medicine, University Medical Center Groningen, Groningen, The Netherlands.
Nordic Bioscience, Biomarkers & Research, Herlev, Denmark.
J Transl Med. 2017 Mar 20;15(1):63. doi: 10.1186/s12967-017-1163-2.
Renal fibrogenesis is associated with increased ECM remodeling and release of collagen fragments in urine in progressive renal disease. We investigated the diagnostic value of urinary collagen degradation products in a proteinuria-driven fibrosis rat model with and without anti-fibrotic S1P-receptor modulator FTY720 treatment.
Proteinuria was induced in male Wistar rats by Adriamycin (ADR) injection (n = 16). Healthy rats served as controls (n = 12). Six weeks post-injection, all underwent renal biopsy, and FTY720-treatment started in ADR-rats (n = 8) and controls (n = 6). Others remained untreated. Rats were sacrificed after 12 weeks. Collagen type I (C1M) and III (C3M) degradation fragments were measured in blood and urine using ELISA. Kidneys were stained for various inflammatory and fibrotic markers.
Six weeks post-injection proteinuria increased (versus controls, P < 0.001) and although no accumulation of interstitial renal collagen type III (iColl3) was observed at this time, urinary C3M (uC3M) and C1M (uC1M) were significantly increased (both P < 0.001). At 12 weeks, uC3M (P < 0.001) and uC1M (P < 0.01) further increased in ADR-rats versus controls, just as fibronectin, PDGF-β receptor, hyaluronan (all P < 0.01), iColl3, PAS, myofibroblasts, macrophages and T-cells (all P < 0.05). FTY720-treatment reduced accumulation of immune cells, α-SMA+ myofibroblasts and PAS-score, but not iColl3 and uC3M. Correlation analyses indicated that uC3M and uC1M reflected and predicted tubulointerstitial fibrogenesis.
These data displayed urinary collagen breakdown products as sensitive early markers of interstitial fibrosis, preceding histological fibrotic changes, which might replace the invasive renal biopsy procedure to assess fibrosis. Anti-fibrotic FTY720 intervention reduced some fibrotic markers without affecting collagen type III metabolism.
在进行性肾病中，肾纤维化与细胞外基质重塑增加及尿中胶原片段释放有关。我们研究了在有或无抗纤维化S1P受体调节剂FTY720治疗的蛋白尿驱动的纤维化大鼠模型中尿胶原降解产物的诊断价值。
通过注射阿霉素（ADR）诱导雄性Wistar大鼠出现蛋白尿（n = 16）。健康大鼠作为对照（n = 12）。注射后6周，所有大鼠均接受肾活检，ADR大鼠（n = 8）和对照大鼠（n = 6）开始接受FTY720治疗。其他大鼠未接受治疗。12周后处死大鼠。使用酶联免疫吸附测定法（ELISA）检测血液和尿液中的I型胶原（C1M）和III型胶原（C3M）降解片段。对肾脏进行各种炎症和纤维化标志物染色。
注射后6周蛋白尿增加（与对照组相比，P < 0.001），尽管此时未观察到肾间质III型胶原（iColl3）的积累，但尿C3M（uC3M）和C1M（uC1M）显著增加（均P < 0.001）。在12周时，与对照组相比，ADR大鼠的uC3M（P < 0.001）和uC1M（P < 0.01）进一步增加，纤连蛋白、血小板衍生生长因子-β受体、透明质酸（均P < 0.01）、iColl3、过碘酸希夫反应（PAS）、肌成纤维细胞、巨噬细胞和T细胞（均P < 0.05）也是如此。FTY720治疗减少了免疫细胞、α-SMA+肌成纤维细胞的积累和PAS评分，但未减少iColl3和uC3M。相关性分析表明，uC3M和uC1M反映并预测了肾小管间质纤维化。
这些数据显示尿胶原分解产物是间质纤维化的敏感早期标志物，早于组织学纤维化改变，这可能取代侵入性肾活检程序来评估纤维化。抗纤维化FTY720干预减少了一些纤维化标志物，但不影响III型胶原代谢。
