Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Sci Rep. 2022 Aug 26;12(1):14598. doi: 10.1038/s41598-022-18825-1.
Long-term administration of lithium is associated with chronic interstitial fibrosis that is partially reduced with exposure to amiloride. We examined potential pathways of how amiloride may reduce interstitial fibrosis. Amiloride was administered to a rat model of lithium induced interstitial fibrosis over a long term (6 months), as well as for short terms of 14 and 28 days. Kidney cortical tissue was subjected to RNA sequencing and microRNA expression analysis. Gene expression changes of interest were confirmed using immunohistochemistry on kidney tissue. Pathways identified by RNA sequencing of kidney tissue were related to 'promoting inflammation' for lithium and 'reducing inflammation' for amiloride. Validation of candidate genes found amiloride reduced inflammatory components induced by lithium including NF-κB/p65 and activated pAKT, and increased p53 mediated regulatory function through increased p21 in damaged tubular epithelial cells. Amiloride also reduced the amount of Notch1 positive PDGFrβ pericytes and infiltrating CD3 cells in the interstitium. Thus, amiloride attenuates a multitude of pro-inflammatory components induced by lithium. This suggests amiloride could be repurposed as a possible anti-inflammatory, anti-fibrotic agent to prevent or reduce the development of chronic interstitial fibrosis.
长期服用锂会导致慢性间质纤维化，而暴露于阿米洛利可部分减轻这种纤维化。我们研究了阿米洛利可能减少间质纤维化的潜在途径。将阿米洛利给予锂诱导的间质纤维化大鼠模型长期（6 个月）以及短期（14 天和 28 天）给药。对肾脏皮质组织进行 RNA 测序和 microRNA 表达分析。使用肾脏组织免疫组织化学验证感兴趣的基因表达变化。肾脏组织 RNA 测序鉴定的途径与锂的“促进炎症”和阿米洛利的“减少炎症”有关。对候选基因的验证发现，阿米洛利减少了锂诱导的炎症成分，包括 NF-κB/p65 和激活的 pAKT，并通过增加受损肾小管上皮细胞中的 p21 增加了 p53 介导的调节功能。阿米洛利还减少了 Notch1 阳性 PDGFrβ 周细胞和间质浸润的 CD3 细胞的数量。因此，阿米洛利减轻了锂诱导的多种促炎成分。这表明阿米洛利可以被重新用作一种潜在的抗炎、抗纤维化药物，以预防或减少慢性间质纤维化的发展。
