Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease.
Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease.
复制标题
DOI：
10.14814/phy2.15652
复制
发表时间：
2023-04
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
--
作者：
常染色体显性遗传性多囊肾病（ADPKD）的发展涉及肾上皮细胞异常。囊液中含有高水平的ATP，除其他作用外，还导致囊肿衬里细胞中电解质的重吸收减少，从而导致囊液积聚。早些时候，我们证明了Pkd 1 RC/RC小鼠，一种ADPKD的亚形态模型，表现出泛连接蛋白-1的表达增加，泛连接蛋白-1是一种能够释放ATP的膜通道。在目前的研究中，我们发现人类ADPKD囊性上皮比正常集合管具有更高的pannexin-1丰度。我们假设丙磺舒抑制泛连接蛋白-1功能可用于减轻ADPKD的发展。在9至20月龄之间监测雄性和雌性Pkd 1 RC/RC和对照小鼠的肾功能。为了测试丙磺舒（一种促尿酸排泄剂和泛连接蛋白-1阻断剂）的治疗效果，在雄性和雌性Pkd 1 RC/RC小鼠中植入渗透微型泵，并给予丙磺舒或溶剂42天，直至1岁。丙磺舒治疗改善了肾小球滤过率，减缓了雄性小鼠肾囊肿的形成（如组织病理学所示）。丙磺舒对钠重吸收和液体转运的机制作用在经受短路电流测量的极化mpkCCDcl 4细胞上以及在基质胶中生长的3D囊肿中进行测试。在mpkCCDc 14上皮细胞系中，丙磺舒引起更高的ENaC电流并减弱体外囊肿形成，表明囊肿中钠含量更低，液体潴留更少。我们的研究为靶向泛连接蛋白-1在ADPKD病理学中的研究开辟了新的途径。丙磺舒抑制泛连接蛋白介导的ATP释放到ADPKD囊肿中。
Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst‐lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1 RC/RC mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin‐1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin‐1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin‐1 function with probenecid can be used to attenuate ADPKD development. Renal function in male and female Pkd1 RC/RC and control mice was monitored between 9 and 20 months of age. To test the therapeutic effects of probenecid (a uricosuric agent and a pannexin‐1 blocker), osmotic minipumps were implanted in male and female Pkd1 RC/RC mice, and probenecid or vehicle was administered for 42 days until 1 year of age. Probenecid treatment improved glomerular filtration rates and slowed renal cyst formation in male mice (as shown in histopathology). The mechanistic effects of probenecid on sodium reabsorption and fluid transport were tested on polarized mpkCCDcl4 cells subjected to short‐circuit current measurements, and in 3D cysts grown in Matrigel. In the mpkCCDcl4 epithelial cell line, probenecid elicited higher ENaC currents and attenuated in vitro cyst formation, indicating lower sodium and less fluid retention in the cysts. Our studies open new avenues of research into targeting pannexin‐1 in ADPKD pathology. Probenecid inhibits pannexin‐mediated ATP release into ADPKD cysts.