Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Taipei Medical University (TMU) Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Life Sci. 2022 Nov 15;309:120992. doi: 10.1016/j.lfs.2022.120992. Epub 2022 Sep 23.
Phosphodiesterase 5 inhibitors (PDE5is) inhibit the hydrolysis of cyclic guanosine 5'-monophosphate in smooth muscle cells and are a widely known treatment for erectile dysfunction. Accumulating evidence also suggests that PDE5is exhibit potential benefits in cardiovascular and chronic kidney diseases. In this study, we examined the therapeutic effects of a PDE5i, vardenafil (VAR), in a focal segmental glomerulosclerosis (FSGS) mouse model.
FSGS was induced in BALB/c mice by the intravenous administration of Adriamycin (AD, 11 mg/kg of body weight). After 24 h, VAR (at 12.5 μg/ml) was given in drinking water ad libitum until the animals were sacrificed. At the end of the experiment, plasma and kidney samples were harvested to evaluate clinical parameters, histopathological changes, and alterations in transcriptome and protein expressions.
In this study, VAR treatment attenuated the deterioration of proteinuria, renal dysfunction, and hypercholesterolemia in AD-induced FSGS. Treatment with VAR exhibited reductions in the severity of both glomerulosclerosis and tubulointerstitial injury in the histological analysis. In addition to relieving AD-induced podocyte loss, VAR also preserved endothelial cells in glomerular capillaries and ameliorated the accumulation of collagen fibers in the mesangial area and Bowman's capsule basement membrane. In addition, VAR showed an ability to suppress transforming growth factor-β-induced fibroblast-to-myofibroblast transdifferentiation.
Our data suggest that VAR exhibited reno-therapeutic effects via attenuating podocyte loss, preserving the integrity of the glomerular vasculature, and ameliorating fibrotic changes. These findings suggest that PDE5is might be a promising treatment modality for nephrotic syndrome.
磷酸二酯酶 5 抑制剂（PDE5is）抑制平滑肌细胞中环鸟苷酸 5'-单磷酸的水解，是治疗勃起功能障碍的常用方法。越来越多的证据表明，PDE5is 在心血管和慢性肾脏病中也具有潜在的益处。在本研究中，我们研究了 PDE5i 伐地那非（VAR）在局灶节段性肾小球硬化（FSGS）小鼠模型中的治疗作用。
通过静脉注射阿霉素（AD，11mg/kg 体重）在 BALB/c 小鼠中诱导 FSGS。24 小时后，VAR（12.5μg/ml）在饮用水中自由饮用，直至动物被处死。实验结束时，采集血浆和肾脏样本，以评估临床参数、组织病理学变化以及转录组和蛋白质表达的改变。
在本研究中，VAR 治疗减轻了 AD 诱导的 FSGS 中蛋白尿、肾功能不全和高胆固醇血症的恶化。VAR 治疗可减轻肾小球硬化和肾小管间质损伤的严重程度。除了缓解 AD 诱导的足细胞丢失外，VAR 还可保留肾小球毛细血管内皮细胞，并改善系膜区和鲍曼囊基底膜胶原纤维的堆积。此外，VAR 显示出抑制转化生长因子-β诱导的成纤维细胞向肌成纤维细胞转分化的能力。
我们的数据表明，VAR 通过减轻足细胞丢失、维持肾小球血管完整性和改善纤维化变化，发挥肾治疗作用。这些发现表明 PDE5is 可能是治疗肾病综合征的一种有前途的治疗方法。
