Brain-Derived Neurotrophic Factor and Supraoptic Vasopressin Neurons in Hyponatremia

Abstract

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 GABA A 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.

Effects of bile duct ligation on the inhibitory control of supraoptic vasopressin neurons

“…This was consistent with our previous studies. 17,18,39,41 Also, plasma osmolality and hematocrit values in the BDL rats were significantly lower than those from sham rats.…”

“…phospho-KCC2 (pKCC2). 39 This was associated with the increased plasma AVP and dilutional hyponatremia observed in liver cirrhosis.…”

“…This could contribute to the sustained elevation of plasma AVP during a worsening hypoosmolar state. We previously reported that during liver cirrhosis, there is an increased expression of BDNF in the SON that leads to increased levels of phosphorylated TrKB (pTrKB) and downregulation of phospho‐KCC2 (pKCC2) 39 . This was associated with the increased plasma AVP and dilutional hyponatremia observed in liver cirrhosis.…”

“…Furthermore, BDNF knockdown in BDL rats prevented the downregulation of pKCC2 and decreased plasma AVP concentration, suggesting a possible involvement of chloride cotransporters in the increased plasma AVP and dilutional hyponatremia observed in BDL rats. 39 The cation chloride cotransporters, KCC2 and NKCC1 are vital to chloride homeostasis and normal inhibitory control in neurons. During the development of the central nervous system, there are changes in the expression of these chloride cotransporters that influence how neurons respond to GABA.…”

Sex Differences in the Regulation of Vasopressin and Oxytocin Secretion in Bile Duct-Ligated Rats

“…Fluid intake and urine excretion were greater in BDL rats despite their low plasma osmolalities, suggesting a possible role for non-osmotic mechanisms in drinking behavior of BDL rats. Previous studies from our laboratory have shown that angiotensin type 1 receptors in the subfornical organ and BDNF in the SON contribute to increased fluid intake in male BDL rats [10, 32, 45, 57]. Sex differences were observed in fluid intake and urine excretion of BDL rats.…”