糖皮質激素受體在腎臟集尿管細胞中參與並維持抗利尿激素之反應

Abstract

抗利尿激素 (vasopressin，簡稱AVP) 會藉由調控第二型水通道蛋白 (aquaporin-2，簡稱AQP2) 來促進腎臟集尿管中的水分再吸收，AVP刺激下，會增加集尿管細胞中整體AQP2的表現量，並且觸發AQP2往細胞尖頂膜 (apical membrane) 運送，因而增加集尿管細胞的水分通透性。我們先前的研究發現，糖皮質激素受體 (glucocorticoid receptor，簡稱GR) 的活化劑地塞米松 (dexamethasone) 會增加集尿管細胞mpkCCD中AVP誘導的AQP2基因表現，代表GR在AVP刺激下AQP2基因表現上扮演著重要的角色。然而，GR是如何增加AVP誘導的AQP2基因表現並不清楚，在本篇研究中，我們提供可以支持兩個GR調控AVP刺激下AQP2基因表現機制的證據。首先，AVP刺激下，GR的活化輔助因子-輔肌動蛋白4 (-actinin 4) 會進入細胞核內，並協助GR增加AQP2的啟動子活性。第二，GR會維持參與「抗利尿激素調控之水分再吸收」路徑中基因的表現，並抑制參與「雌激素 (estrogen) 訊息傳遞路徑」、「腫瘤壞死因子 (tumor necrosis factor, 簡稱TNF) 訊息傳遞路徑」和「乙型轉化因子 (transforming growth factor-beta, 簡稱TGF-) 訊息傳遞路徑」之基因的表現，這些訊息路徑已知會抑制AQP2基因表現。綜合以上結果，在mpkCCD細胞中，GR會藉由-actinin 4的協助而加強AVP誘導的AQP2基因表現，並維持參與AVP反應和AQP2基因表現之基因的表現。

Vasopressin (AVP) is an antidiuretic hormone that induces water reabsorption by regulating a water channel protein, aquaporin-2 (AQP2), in the kidney collecting ducts. AVP increases overall AQP2 gene expression and triggers AQP2 apical trafficking, thereby increasing water permeability in the collecting duct cells. Our previous study showed that dexamethasone, a glucocorticoid receptor (GR) agonist, enhanced AVP-induced AQP2 gene expression in the collecting duct mpkCCD cells, indicative of a role of GR in AVP-induced AQP2 gene expression. However, how GR mediates AVP-induced AQP2 gene expression was unknown. Here, we provide evidence supporting two mechanisms of GR-mediated AVP-induced AQP2 gene expression. First, in response to AVP, the GR co-activator -actinin 4 translocated into the nucleus and assisted GR to increase AQP2 promoter activity. Second, GR maintained expression of genes involved in “vasopressin-regulated water reabsorption” and repressed expression of genes involved in “estrogen signaling pathway”, “TNF signaling pathway”, and “TGF- signaling pathway” known to suppress AQP2 gene expression. Taken together, these results implicated that GR, assisted by -actinin 4, potentiates AVP-induced AQP2 gene expression and maintains transcriptome profile that permits AVP responses and AQP2 gene expression in the mpkCCD cells.