Department of Physiology and Anatomy, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA.
Department of Physiology and Anatomy, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA,
Neuroendocrinology. 2020;110(7-8):630-641. doi: 10.1159/000503723. Epub 2019 Sep 27.
Hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in liver failure patients. The mechanisms causing dysregulation of AVP secretion are unknown. Our hypothesis is that inappropriate AVP release associated with liver failure is due to increased brain-derived neurotrophic factor (BDNF) in the supraoptic nucleus (SON). BDNF diminishes GABAA inhibition in SON AVP neurons by increasing intracellular chloride through tyrosine receptor kinase B (TrkB) activation and downregulation of K+/Cl- cotransporter 2 (KCC2). This loss of inhibition could increase AVP secretion. This hypothesis was tested using shRNA against BDNF (shBDNF) in the SON in bile duct ligated (BDL) male rats. All BDL rats had significantly increased liver weight (p < 0.05; 6-9) compared to shams. BDL rats with control -shRNA injections (BDL scrambled [SCR]) developed hyponatremia with increased plasma AVP and copeptin (CPP; all p < 0.05; 6-9) compared to sham groups. This is the first study to show that phosphorylation of TrkB is significantly increased along with significant decrease in phosphorylation of KCC2 in BDL SCR rats compared to the sham rats (p < 0.05;6-8). Knockdown of BDNF in the SON of BDL rats (BDL shBDNF) significantly increased plasma osmolality and hematocrit compared to BDL SCR rats (p < 0.05; 6-9). The BDL shBDNF rats had significant (p < 0.05; 6-9) decreases in plasma AVP and CPP concentration compared to BDL SCR rats. The BDNF knockdown also significantly blocked the increase in TrkB phosphorylation and decrease in KCC2 phosphorylation (p < 0.05; 6-8). The results indicate that BDNF produced in the SON contributes to increased AVP secretion and hyponatremia during liver failure.
由于精氨酸血管加压素（AVP）分泌增加导致的低钠血症会增加肝衰竭患者的死亡率。导致 AVP 分泌失调的机制尚不清楚。我们的假设是，与肝衰竭相关的不适当 AVP 释放是由于视上核（SON）中脑源性神经营养因子（BDNF）的增加。BDNF 通过激活酪氨酸受体激酶 B（TrkB）并下调 K + / Cl-共转运蛋白 2（KCC2）来增加细胞内氯离子，从而减弱 SON AVP 神经元中的 GABA 抑制。这种抑制的丧失可能会增加 AVP 的分泌。该假说通过在胆管结扎（BDL）雄性大鼠的 SON 中使用 BDNF（shBDNF）进行 shRNA 来测试。与 sham 组相比，所有 BDL 大鼠的肝重均显著增加（p <0.05；6-9）。与 sham 组相比，接受对照-shRNA 注射（BDL 随机 [SCR]）的 BDL 大鼠出现低钠血症，血浆 AVP 和 copeptin（CPP；所有 p <0.05；6-9）均增加。这是第一项表明 BDL SCR 大鼠与 sham 大鼠相比，TrkB 的磷酸化显着增加，而 KCC2 的磷酸化显着降低的研究（p <0.05；6-8）。BDL 大鼠 SON 中的 BDNF 敲低（BDL shBDNF）与 BDL SCR 大鼠相比，显著增加了血浆渗透压和红细胞压积（p <0.05；6-9）。BDL shBDNF 大鼠的血浆 AVP 和 CPP 浓度显着降低（p <0.05；6-9）与 BDL SCR 大鼠相比。BDNF 敲低还显着阻断了 TrkB 磷酸化的增加和 KCC2 磷酸化的减少（p <0.05；6-8）。结果表明，SON 中产生的 BDNF 有助于增加肝衰竭期间的 AVP 分泌和低钠血症。
