Jadot Inès, Colombaro Vanessa, Martin Blanche, Habsch Isabelle, Botton Olivia, Nortier Joëlle, Declèves Anne-Emilie, Caron Nathalie
Molecular Physiology Research Unit - URPhyM, NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), Namur, Belgium.
Nephrology Department, Erasme Academic Hospital and Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
PLoS One. 2017 Aug 23;12(8):e0183604. doi: 10.1371/journal.pone.0183604. eCollection 2017.
Aristolochic Acid (AA) nephropathy (AAN) is a progressive tubulointerstitial nephritis characterized by an early phase of acute kidney injury (AKI) leading to chronic kidney disease (CKD). The reduced nitric oxide (NO) bioavailability reported in AAN might contribute to renal function impairment and progression of the disease. We previously demonstrated that L-arginine (L-Arg) supplementation is protective in AA-induced AKI. Since the severity of AKI may be considered a strong predictor of progression to CKD, the present study aims to assess the potential benefit of L-Arg supplementation during the transition from the acute phase to the chronic phase of AAN. C57BL/6J male mice were randomly subjected to daily i.p. injections of vehicle or AA for 4 days. To determine whether renal AA-induced injuries were linked to reduced NO production, L-Arg was added to drinking water from 7 days before starting i.p. injections, until the end of the protocol. Mice were euthanized 5, 10 and 20 days after vehicle or AA administration. AA-treated mice displayed marked renal injury and reduced NO bioavailability, while histopathological features of AAN were reproduced, including interstitial cell infiltration and tubulointerstitial fibrosis. L-Arg treatment restored renal NO bioavailability and reduced the severity of AA-induced injury, inflammation and fibrosis. We concluded that reduced renal NO bioavailability contributes to the processes underlying AAN. Furthermore, L-Arg shows nephroprotective effects by decreasing the severity of acute-to-chronic transition in experimental AAN and might represent a potential therapeutic tool in the future.
马兜铃酸（AA）肾病（AAN）是一种进行性肾小管间质性肾炎，其特征是早期急性肾损伤（AKI）阶段会发展为慢性肾脏病（CKD）。AAN中报道的一氧化氮（NO）生物利用度降低可能导致肾功能损害和疾病进展。我们之前证明补充L-精氨酸（L-Arg）对AA诱导的AKI具有保护作用。由于AKI的严重程度可能被视为进展为CKD的有力预测指标，因此本研究旨在评估在AAN从急性期过渡到慢性期期间补充L-Arg的潜在益处。将C57BL/6J雄性小鼠随机分为两组，每天腹腔注射溶剂或AA，持续4天。为了确定肾脏AA诱导的损伤是否与NO生成减少有关，从开始腹腔注射前7天至实验结束，在饮水中添加L-Arg。在给予溶剂或AA后5、10和20天对小鼠实施安乐死。接受AA治疗的小鼠表现出明显的肾损伤和NO生物利用度降低，同时重现了AAN的组织病理学特征，包括间质细胞浸润和肾小管间质纤维化。L-Arg治疗恢复了肾脏NO生物利用度，并减轻了AA诱导的损伤、炎症和纤维化的严重程度。我们得出结论，肾脏NO生物利用度降低是AAN发病机制的一部分。此外，L-Arg通过减轻实验性AAN中急性到慢性转变的严重程度显示出肾保护作用，可能成为未来一种潜在的治疗手段。
