Trant Jordan, Sanchez Gladis, McDermott Jeffery P, Blanco Gustavo
Department of Cell Biology and Physiology and the Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Cell Biology and Physiology and the Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
Exp Cell Res. 2025 Jan 1;444(1):114356. doi: 10.1016/j.yexcr.2024.114356. Epub 2024 Nov 23.
We have previously shown that the hormone ouabain is a circulating factor which can accelerate the progression of autosomal dominant polycystic kidney disease (ADPKD). At physiologic concentrations, ouabain increases cyst area and fibrosis in kidneys from ADPKD but not wildtype mice. These effects are due to an increased affinity for ouabain by its receptor, Na,K-ATPase (NKA), in the kidneys of ADPKD mice which leads to over-activation of NKA signaling function. Previous studies suggested that ouabain's stimulation of NKA signal transduction is mediated by NKA located within cell caveolae. Here, we determined whether caveolae are involved in the ouabain-induced progression of ADPKD cysts. We generated an ADPKD mouse with a global knockout of the main structural component of caveolae, caveolin-1 (CAV1), which we confirmed lacks caveolae in the kidney. When given physiological amounts of ouabain for 5 months, Pkd1Cav1 mice did not exhibit any changes in cyst progression, contrasting with the Pkd1 mice which showed a significant increase in cystic area and kidney fibrosis. Also, measures of ouabain-induced cell proliferation, including the number of Ki67-positive nuclei and phosphorylation of the extracellular regulated kinase (ERK) and protein kinase B (Akt), did not increase in the Pkd1Cav1 mice compared with the Pkd1 mice. Moreover, the abnormally increased affinity for ouabain of NKA in Pkd1 mice was restored to wildtype levels in the Pkd1Cav1 mice. This work highlights the role of caveolae in ouabain-induced NKA signaling and ADPKD cyst progression.
我们之前已经表明，激素哇巴因是一种循环因子，可加速常染色体显性多囊肾病（ADPKD）的进展。在生理浓度下，哇巴因可增加ADPKD小鼠而非野生型小鼠肾脏中的囊肿面积和纤维化。这些作用是由于ADPKD小鼠肾脏中其受体钠钾ATP酶（NKA）对哇巴因的亲和力增加，导致NKA信号功能过度激活。先前的研究表明，哇巴因对NKA信号转导的刺激是由位于细胞小窝内的NKA介导的。在此，我们确定细胞小窝是否参与哇巴因诱导的ADPKD囊肿进展。我们培育了一种全局敲除细胞小窝主要结构成分小窝蛋白-1（CAV1）的ADPKD小鼠，我们证实其肾脏中缺乏细胞小窝。给予生理量的哇巴因5个月后，Pkd1Cav1小鼠的囊肿进展未出现任何变化，这与显示囊肿面积和肾脏纤维化显著增加的Pkd1小鼠形成对比。此外，与Pkd1小鼠相比，Pkd1Cav1小鼠中哇巴因诱导的细胞增殖指标，包括Ki67阳性细胞核数量、细胞外调节激酶（ERK）和蛋白激酶B（Akt）的磷酸化，均未增加。此外，Pkd1小鼠中NKA对哇巴因异常增加的亲和力在Pkd1Cav1小鼠中恢复到了野生型水平。这项工作突出了细胞小窝在哇巴因诱导的NKA信号传导和ADPKD囊肿进展中的作用。
