Abstract
Pre-eclampsia is a hypertensive disorder of pregnancy characterised by hypertension and sodium retention by the kidneys. To identify changes in sodium uptake proteins in the tubules of the distal nephron, we studied their expression in urinary extracellular vesicles or exosomes (uEVs). Urine was collected from women with pre-eclampsia or during normal pregnancy, and from healthy non-pregnant controls. uEVs were isolated by centrifugation and analyzed by Western blot. Expression, proteolytic cleavage and phosphorylation was determined by densitometric analysis normalized to the exosome marker CD9. Results showed a significant increase in phosphorylation of the activating S130 site in NKCC2, the drug target for frusemide, in women with pre-eclampsia compared with normal pregnant women. Phosphorylation of the activating sites T101/105 in NKCC2 was similar but the activating T60 site in NCC, the drug target for thiazide diuretics, showed significantly less phosphorylation in pre-eclampsia compared with normal pregnancy. Expression of the larger forms of the α subunit of ENaC, the drug target for amiloride, was significantly greater in pre-eclampsia, with more fragmentation of theγ subunit. The differences observed are predicted to increase the activity of NKCC2 and ENaC while reducing that of NCC. This will increase sodium reabsorption, and so contribute to hypertension in pre-eclampsia.
Highlights
Pre-eclampsia complicates 3–8% of pregnancies resulting in significant maternal, fetal and neonatal morbidity and mortality [1]
Generalized edema is a common manifestation of pre-eclampsia, with proteinuric patients displaying avid sodium retention, which occurs despite suppression of the reninangiotensin-aldosterone system and intravascular contraction [4, 5]
NKCC2 and Na-Cl co-transporter (NCC) are activated by phosphorylation, which is associated with surface expression and regulated primarily by the WNK-SPAK/OSR-1 pathway [7]
Summary
Pre-eclampsia complicates 3–8% of pregnancies resulting in significant maternal, fetal and neonatal morbidity and mortality [1]. The sodium transporters responsible for sodium retention in pre-eclampsia are unknown, the most important transporters affecting renal sodium reabsorption in inherited disorders of hypo- or hypertension are the Na-Cl2-K co-transporter 2 (NKCC2), the Na-Cl co-transporter (NCC) and the epithelial sodium channel (ENaC) [6]. These proteins are found on the apical surface of unique areas of the distal nephron, and are the drug targets for loop diuretics, thiazide diuretics, and amiloride, respectively. NCC is phosphorylated at three residues by SPAK and OSR-1, but the T60 phosphosite appears to be the most important for co-transporter activity [12]
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