Gosmanov Aidar R, Schneider Edward G, Thomason Donald B
Department of Physiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Am J Physiol Regul Integr Comp Physiol. 2003 Mar;284(3):R655-65. doi: 10.1152/ajpregu.00576.2002. Epub 2002 Nov 14.
In isosmotic conditions, insulin stimulation of PI 3-K/Akt and p38 MAPK pathways in skeletal muscle inhibits Na(+)-K(+)-2Cl(-) cotransporter (NKCC) activity induced by the ERK1,2 MAPK pathway. Whether these signaling cascades contribute to NKCC regulation during osmotic challenge is unknown. Increasing osmolarity by 20 mosM with either glucose or mannitol induced NKCC-mediated (86)Rb uptake and water transport into rat soleus and plantaris skeletal muscle in vitro. This NKCC activity restored intracellular water. In contrast to mannitol, hyperosmolar glucose increased ERK1,2 and p38 MAPK phosphorylation. Glucose, but not mannitol, impaired insulin-stimulated phosphorylation of Akt and p38 MAPK in the plantaris and soleus muscles, respectively. Hyperosmolarity-induced NKCC activation was insensitive to insulin action and pharmacological inhibition of ERK1,2 and p38 MAPK pathways. Paradoxically, cAMP-producing agents, which stimulate NKCC activity in isosmotic conditions, suppressed hyperosmolar glucose- and mannitol-induced NKCC activity and prevented restoration of muscle cell volume in hyperosmotic media. These results indicate that NKCC activity helps restore muscle cell volume during hyperglycemia. Moreover, hyperosmolarity activates NKCC regulatory pathways that are insensitive to insulin inhibition.
在等渗条件下，胰岛素对骨骼肌中PI 3-K/Akt和p38 MAPK信号通路的刺激会抑制由ERK1,2 MAPK信号通路诱导的Na(+)-K(+)-2Cl(-)共转运体（NKCC）的活性。这些信号级联在渗透压挑战期间是否参与NKCC的调节尚不清楚。用葡萄糖或甘露醇将渗透压增加20 mosM可在体外诱导大鼠比目鱼肌和跖肌中NKCC介导的(86)Rb摄取和水转运。这种NKCC活性可恢复细胞内水分。与甘露醇不同，高渗葡萄糖可增加ERK1,2和p38 MAPK的磷酸化水平。葡萄糖而非甘露醇分别损害了胰岛素刺激的跖肌和比目鱼肌中Akt和p38 MAPK的磷酸化。高渗诱导的NKCC激活对胰岛素作用以及ERK1,2和p38 MAPK信号通路的药理学抑制均不敏感。矛盾的是，在等渗条件下刺激NKCC活性的cAMP生成剂可抑制高渗葡萄糖和甘露醇诱导的NKCC活性，并防止高渗培养基中肌肉细胞体积的恢复。这些结果表明，NKCC活性有助于在高血糖期间恢复肌肉细胞体积。此外，高渗激活了对胰岛素抑制不敏感的NKCC调节通路。
