Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
PLoS One. 2020 Dec 17;15(12):e0244251. doi: 10.1371/journal.pone.0244251. eCollection 2020.
The connexin 37 (Cx37) channel is clustered at gap junctions between cells in the renal vasculature or the renal tubule where it is abundant in basolateral cell interdigitations and infoldings of epithelial cells in the proximal tubule, thick ascending limb, distal convoluted tubule and collecting duct; however, physiological data regarding its role are limited. In this study, we investigated the role of Cx37 in fluid homeostasis using mice with a global deletion of Cx37 (Cx37-/- mice). Under baseline conditions, Cx37-/- had ~40% higher fluid intake associated with ~40% lower urine osmolality compared to wild-type (WT) mice. No differences were observed between genotypes in urinary adenosine triphosphate or prostaglandin E2, paracrine factors that alter renal water handling. After 18-hours of water deprivation, plasma aldosterone and urine osmolality increased significantly in Cx37-/- and WT mice; however, the latter remained ~375 mmol/kg lower in Cx37-/- mice, an effect associated with a more pronounced body weight loss despite higher urinary AVP/creatinine ratios compared to WT mice. Consistent with this, fluid intake in the first 3 hours after water deprivation was 37% greater in Cx37-/- vs WT mice. Cx37-/- mice showed significantly lower renal AQP2 abundance and AQP2 phosphorylation at serine 256 than WT mice in response to vehicle or dDAVP, suggesting a partial contribution of the kidney to the lower urine osmolality. The abundance and responses of the vasopressin V2 receptor, AQP3, NHE3, NKCC2, NCC, H+-ATPase, αENaC, γENaC or Na+/K+-ATPase were not significantly different between genotypes. In summary, these results demonstrate that Cx37 is important for body water handling.
间隙连接蛋白 37（Cx37）通道在肾脏血管或肾小管的细胞间隙连接中聚集，在近端肾小管、厚升支、远端卷曲小管和集合管中，Cx37 在基底外侧细胞的相互交错和上皮细胞的内褶中丰富存在；然而，关于其作用的生理数据有限。在这项研究中，我们使用全身缺失 Cx37 的小鼠（Cx37-/- 小鼠）研究了 Cx37 在液体稳态中的作用。在基础条件下，与野生型（WT）小鼠相比，Cx37-/- 小鼠的液体摄入量高约 40%，尿液渗透压低约 40%。在基因型之间，尿液中三磷酸腺苷或前列腺素 E2 没有差异，这些旁分泌因子会改变肾脏的水分处理。在 18 小时的水剥夺后，Cx37-/- 和 WT 小鼠的血浆醛固酮和尿液渗透压显著增加；然而，Cx37-/- 小鼠的尿液渗透压仍低约 375mmol/kg，尽管与 WT 小鼠相比，尿液 AVP/肌酐比值更高，但这种差异与更明显的体重减轻有关。与此一致的是，与 WT 小鼠相比，Cx37-/- 小鼠在水剥夺后 3 小时内的液体摄入量增加了 37%。与 WT 小鼠相比，Cx37-/- 小鼠在给予载体或 dDAVP 后，肾脏 AQP2 丰度和 AQP2 丝氨酸 256 磷酸化明显降低，表明肾脏对低尿渗透压有一定的贡献。血管加压素 V2 受体、AQP3、NHE3、NKCC2、NCC、H+-ATPase、αENaC、γENaC 或 Na+/K+-ATPase 的丰度和反应在基因型之间没有显著差异。总之，这些结果表明 Cx37 对体液处理很重要。
