Division of Nephrology and Hypertension, Department of Medicine and USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Am J Physiol Renal Physiol. 2022 Jan 1;322(1):F27-F41. doi: 10.1152/ajprenal.00298.2021. Epub 2021 Nov 22.
Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the polycystin 1 () or polycystin 2 genes, presents with progressive development of kidney cysts and eventual end-stage kidney disease with limited treatment options. Previous work has shown that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of cystic fibrosis transmembrane conductance regulator-mediated fluid secretion, mammalian target of rapamycin, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant mouse model, homozygous for the R3277C knockin point mutation in the gene. This mutation causes ADPKD in humans. male and female mice, which have a slow progression to end-stage kidney disease, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 mo of age. As previously reported, females had a more severe disease phenotype as compared with males. Metformin treatment reduced the ratio of total kidney weight-to-body weight relative to age-matched and sex-matched untreated controls at both 9 and 12 mo and reduced the cystic index in females at 9 mo. Metformin also increased glomerular filtration rate, lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 versus untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients. Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.
常染色体显性多囊肾病（ADPKD）由多囊蛋白 1（PC1）或多囊蛋白 2 基因的突变引起，其特征为肾囊肿进行性发展，最终导致终末期肾病，且治疗选择有限。先前的研究表明，二甲双胍通过抑制囊性纤维化跨膜电导调节蛋白介导的液体分泌、哺乳动物雷帕霉素靶蛋白和 cAMP 通路，减少快速 ADPKD 小鼠模型中的囊肿生长。本研究重要地测试了二甲双胍作为一种治疗更具临床相关性的 R3277C 基因点突变纯合子 ADPKD 小鼠模型的疗效，该突变导致人类 ADPKD。3 至 9 或 12 个月大时，雄性和雌性接受二甲双胍（饮用水中 300mg/kg/天，与单独用水相比）治疗。正如之前报道的，与雄性相比，雌性的疾病表型更为严重。与年龄和性别匹配的未治疗对照组相比，二甲双胍治疗在 9 和 12 个月时降低了总肾重/体重比，并降低了 9 个月时雌性的囊肿指数。与对照组相比，二甲双胍还提高了肾小球滤过率、降低了收缩压、改善了贫血并降低了血尿素氮水平。此外，与未治疗对照组相比，二甲双胍降低了关键炎症标志物的基因表达，以及肾损伤标志物-1 和细胞周期蛋白依赖性激酶-1 的基因和蛋白表达。总之，这些发现表明二甲双胍在这种高度相关的缓慢进展的 ADPKD 小鼠模型中具有多种有益作用，这可能有助于为患者提供新的 ADPKD 治疗方法。
