Gaeggeler Hans-Peter, Gonzalez-Rodriguez Elena, Jaeger Nicole Fowler, Loffing-Cueni Dominique, Norregaard Rikke, Loffing Johannes, Horisberger Jean-Daniel, Rossier Bernard C
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
J Am Soc Nephrol. 2005 Apr;16(4):878-91. doi: 10.1681/ASN.2004121110. Epub 2005 Mar 2.
Aldosterone controls sodium balance by regulating an epithelial sodium channel (ENaC)-mediated sodium transport along the aldosterone-sensitive distal nephron, which expresses both mineralocorticoid (MR) and glucocorticoid receptors (GR). Mineralocorticoid specificity is ensured by 11beta-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol or corticosterone into inactive metabolites that are unable to bind MR and/or GR. The fractional occupancy of MR and GR by aldosterone mediating the sodium transport response in the aldosterone-sensitive distal nephron cannot be studied in vivo. For answering this question, a novel mouse cortical collecting duct cell line (mCCD(cl1)), which expresses significant levels of MR and GR and a robust aldosterone sodium transport response, was used. Aldosterone elicited a biphasic response: Low doses (K(1/2) = approximately 0.5 nM) induced a transient and early increase of sodium transport (peaking at 3 h), whereas high doses (K(1/2) = approximately 90 nM) entailed an approximately threefold larger, long-lasting response. At 3 h, the corticosterone dose-response curve was shifted to the right compared with that of aldosterone by more than two log concentrations, an effect that was fully reverted in the presence of the 11beta-hydroxysteroid dehydrogenase type 2 inhibitor carbenoxolone. Low doses of dexamethasone (0.1 to 1 nM) failed to induce an early response, but high doses elicited a long-lasting response (K(1/2) = approximately 8 nM), similar to that observed for high aldosterone concentrations. Equilibrium binding assays showed that both aldosterone and corticosterone bind to a high-affinity, low-capacity site, whereas dexamethasone binds to one site. Within the physiologic range of aldosterone concentrations, sodium transport is predicted to be controlled by MR occupancy during circadian cycles and by MR and GR occupancy during salt restriction or acute stress.
醛固酮通过调节上皮钠通道（ENaC）介导的沿醛固酮敏感远端肾单位的钠转运来控制钠平衡，醛固酮敏感远端肾单位同时表达盐皮质激素（MR）和糖皮质激素受体（GR）。2型11β-羟基类固醇脱氢酶确保了盐皮质激素的特异性，该酶将皮质醇或皮质酮代谢为无活性的代谢产物，这些代谢产物无法结合MR和/或GR。在体内无法研究醛固酮介导醛固酮敏感远端肾单位钠转运反应时MR和GR的占有率。为了回答这个问题，使用了一种新型的小鼠皮质集合管细胞系（mCCD(cl1)），该细胞系表达高水平的MR和GR，并具有强大的醛固酮钠转运反应。醛固酮引发了双相反应：低剂量（K(1/2) = 约0.5 nM）诱导钠转运短暂且早期增加（在3小时达到峰值），而高剂量（K(1/2) = 约90 nM）则导致约三倍大的持久反应。在3小时时，与醛固酮相比，皮质酮的剂量反应曲线向右移动了超过两个对数浓度，在2型11β-羟基类固醇脱氢酶抑制剂甘珀酸存在下，这种效应完全逆转。低剂量的地塞米松（0.1至1 nM）未能诱导早期反应，但高剂量引发了持久反应（K(1/2) = 约8 nM），类似于高醛固酮浓度时观察到的反应。平衡结合试验表明，醛固酮和皮质酮都与一个高亲和力、低容量位点结合，而地塞米松与一个位点结合。在醛固酮浓度的生理范围内，预计在昼夜节律周期中钠转运由MR占有率控制，在盐限制或急性应激期间由MR和GR占有率控制。
