Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
FASEB J. 2020 Jun;34(6):8296-8309. doi: 10.1096/fj.202000214RR. Epub 2020 May 4.
Uremic cardiomyopathy, characterized by hypertension, cardiac hypertrophy, and fibrosis, is a complication of chronic kidney disease (CKD). Urea transporter (UT) inhibition increases the excretion of water and urea, but the effect on uremic cardiomyopathy has not been studied. We tested UT inhibition by dimethylthiourea (DMTU) in 5/6 nephrectomy mice. This treatment suppressed CKD-induced hypertension and cardiac hypertrophy. In CKD mice, cardiac fibrosis was associated with upregulation of UT and vimentin abundance. Inhibition of UT suppressed vimentin amount. Left ventricular mass index in DMTU-treated CKD was less compared with non-treated CKD mice as measured by echocardiography. Nephrectomy was performed in UT-A1/A3 knockout (UT-KO) to further confirm our finding. UT-A1/A3 deletion attenuates the CKD-induced increase in cardiac fibrosis and hypertension. The amount of α-smooth muscle actin and tgf-β were significantly less in UT-KO with CKD than WT/CKD mice. To study the possibility that UT inhibition could benefit heart, we measured the mRNA of renin and angiotensin-converting enzyme (ACE), and found both were sharply increased in CKD heart; DMTU treatment and UT-KO significantly abolished these increases. Conclusion: Inhibition of UT reduced hypertension, cardiac fibrosis, and improved heart function. These changes are accompanied by inhibition of renin and ACE.
尿毒症性心肌病的特征是高血压、心肌肥厚和纤维化，是慢性肾脏病（CKD）的一种并发症。尿素转运蛋白（UT）抑制可增加水和尿素的排泄，但对尿毒症性心肌病的影响尚未研究。我们在 5/6 肾切除术小鼠中测试了二甲基硫脲（DMTU）对 UT 的抑制作用。这种治疗抑制了 CKD 引起的高血压和心肌肥厚。在 CKD 小鼠中，心脏纤维化与 UT 和波形蛋白丰度的上调有关。UT 的抑制抑制了波形蛋白的含量。通过超声心动图测量，与未治疗的 CKD 小鼠相比，DMTU 治疗的 CKD 小鼠左心室质量指数较低。在 UT-A1/A3 敲除（UT-KO）中进行肾切除术以进一步证实我们的发现。UT-A1/A3 缺失可减轻 CKD 引起的心脏纤维化和高血压增加。与 WT/CKD 小鼠相比，UT-KO 合并 CKD 时α-平滑肌肌动蛋白和 tgf-β 的含量明显减少。为了研究 UT 抑制可能有益于心脏的可能性，我们测量了肾素和血管紧张素转换酶（ACE）的 mRNA，发现 CKD 心脏中的这两种物质都急剧增加；DMTU 治疗和 UT-KO 显著消除了这些增加。结论：UT 抑制可降低高血压、心脏纤维化，改善心功能。这些变化伴随着肾素和 ACE 的抑制。
