Nørgård Mikkel Ø, Christensen Michael, Mutsaers Henricus A M, Nørregaard Rikke
Department of Clinical Medicine, Aarhus University, N 8200 Aarhus, Denmark.
Pharmaceutics. 2020 Mar 26;12(4):301. doi: 10.3390/pharmaceutics12040301.
Phenformin and metformin are antihyperglycemic drugs that belong to the class of biguanides. Previously, we demonstrated that metformin elicits renoprotective effects in unilateral ureteral obstructed mice by reducing the infiltration of immune cells into the kidney. Since phenformin is a more potent drug as compared to metformin, we investigated the renoprotective properties of phenformin. We studied the efficacy of both drugs using mice that underwent unilateral ureteral obstruction. Renal damage was evaluated on RNA and protein level by qPCR, Western blotting, and immunohistochemistry. Moreover, we studied immune cell infiltration using flow cytometry. Both biguanides significantly reduced UUO-induced kidney injury, as illustrated by a reduction in KIM-1 protein expression. In addition, both metformin and phenformin impacted the gene expression of several inflammatory markers but to a different extent. Moreover, in contrast to metformin, phenformin did not impact immune cell infiltration into UUO kidneys. In conclusion, we demonstrated that phenformin has similar renoprotective effects as metformin, but the mechanism of action differs, and phenformin is more potent. The beneficial effects of phenformin are probably due to inhibition of the STAT3 pathway and mitochondrial complex I. Further research is needed to unveil the therapeutic potential of phenformin for the treatment of renal injury, either at low, non-toxic concentrations or as part of a combination therapy.
苯乙双胍和二甲双胍是属于双胍类的抗高血糖药物。此前，我们证明二甲双胍通过减少免疫细胞向肾脏的浸润，对单侧输尿管梗阻小鼠产生肾脏保护作用。由于苯乙双胍比二甲双胍的药效更强，我们研究了苯乙双胍的肾脏保护特性。我们使用单侧输尿管梗阻的小鼠研究了这两种药物的疗效。通过定量聚合酶链反应（qPCR）、蛋白质免疫印迹法和免疫组织化学在RNA和蛋白质水平评估肾脏损伤。此外，我们使用流式细胞术研究免疫细胞浸润情况。两种双胍类药物均显著减轻了单侧输尿管梗阻诱导的肾损伤，这通过KIM-1蛋白表达的降低得以体现。此外，二甲双胍和苯乙双胍均影响了几种炎症标志物的基因表达，但程度不同。此外，与二甲双胍不同，苯乙双胍并未影响免疫细胞向单侧输尿管梗阻肾脏的浸润。总之，我们证明苯乙双胍与二甲双胍具有相似的肾脏保护作用，但作用机制不同，且苯乙双胍药效更强。苯乙双胍的有益作用可能归因于对信号转导和转录激活因子3（STAT3）通路以及线粒体复合物I的抑制。需要进一步研究以揭示苯乙双胍在低浓度、无毒浓度下或作为联合治疗一部分用于治疗肾损伤的治疗潜力。
