Perinatal Pathologies Associated with Sodium Intake and OS

Perinatal Pathologies Associated with Sodium Intake and OS: Comparison

Please note this is a comparison between Version 1 by Bálint Farkas and Version 2 by Nora Tang.

Excessive sodium intake has been well established as a risk factor for the development and progression of cardiovascular and renal diseases. Its adverse effects are achieved by renal sodium retention and related volume expansion and by inducing low-grade inflammation and oxidative stress (OS) in the target tissues.

salt intake
nonrenal regulation
tissue damage
oxidative stress

1. Preeclamptic Pregnancy

It has long been recognized that high salt intake and sodium retention is a risk factor of preeclampsia. In a randomized, cross-over, double-blinded study, high salt intake was found to decrease renin and angiotensin II concentrations in healthy pregnant and nonpregnant women, but it remained unaltered in patients with preeclampsia. Plasma aldosterone was similarly depressed while brain natriuretic peptide increased in all groups. These observations indicated that in preeclampsia, the renal capacity to excrete sodium is impaired, and more sodium is retained when patients are subjected to high sodium intake [65]. Previously, it has also been shown that patients with proteinuric pregnancy-induced hypertension avidly retain sodium but without apparent influences on plasma renin and aldosterone concentrations [66].

In a cross-sectional study of 569 pregnant women from the Odense Child Cohort, urinary sodium and potassium excretion with plasma levels and urinary aldosterone excretion were measured at 29 weeks of gestation to assess their predictive value of feto-placental development and preeclampsia. Salt intake of more than 6 g/kg proved to be an independent predictor of preeclampsia and pregnancy-induced hypertension whereas aldosterone was significantly associated with placental weight and birth weight. Based on these results, it was concluded that high sodium combined with low potassium intake directly increase the risk of preeclampsia. Indirectly, however, suppressing aldosterone production impairs feto-placental development via reducing VEGF and placental growth factor expression [67]. The protective effects of aldosterone on the function of the feto-placental unit have already been established by others [68,69].

In a recent comprehensive review, Scaife and Hohaupt carefully evaluated the association of preeclampsia, salt intake, and aldosterone production and provided evidence that the placenta, similar to the skin interstitium, functions as a salt-sensitive organ and regulates sodium balance [70]. Indeed, the negatively charged GAGa and proteoglycans (syndecan 2, glycopicans 1,3, decorin, perlecan) are abundantly expressed in the placenta of healthy pregnancy and bind and reversibly store excess sodium [71,72]. Accumulated sodium generates hypertonicity that induces macrophage invasion and activation. Activated macrophages release TonEBP and VEGF-C, leading to lymphangiogenesis and eNOS expression. This sodium reservoir can buffer excess sodium and maintain low vascular resistance and utero-placental perfusion. In preeclampsia, the capacity of this system is markedly reduced and cannot meet the actual sodium (and volume) requirements of utero-placental circulation. It is suggested, therefore, that supplemental NaCl should be provided to reestablish normal plasma volume to compensate for the low aldosterone characteristic of preeclampsia. NaCl supplementation had also been claimed to alter immune milieu by preventing a decrease of CD14 macrophages and the unfavourable cytokine balance that may lead to defective placentation [73].

It should be noted that increased levels of tissue sodium have been shown to enhance the polarization of naïve Th cells to Th17 cells, and via their IL 17 production, they may increase the generation of ROS and proinflammatory cytokines that may limit NO bioavailability [74]. These untoward effects of sodium accumulation in the placental tissue are certainly overcome by the benefit of the activation of TonEBP-VEGF-C-eNOS pathways [75].

It has long been recognized that high salt intake and sodium retention is a risk factor of preeclampsia. In a randomized, cross-over, double-blinded study, high salt intake was found to decrease renin and angiotensin II concentrations in healthy pregnant and nonpregnant women, but it remained unaltered in patients with preeclampsia. Plasma aldosterone was similarly depressed while brain natriuretic peptide increased in all groups. These observations indicated that in preeclampsia, the renal capacity to excrete sodium is impaired, and more sodium is retained when patients are subjected to high sodium intake ^[1]. Previously, it has also been shown that patients with proteinuric pregnancy-induced hypertension avidly retain sodium but without apparent influences on plasma renin and aldosterone concentrations ^[2].

2. Prenatal High Sodium Intake and Vascular Programming

The concept of the developmental origin of certain chronic diseases in adulthood was conceived by Barker and coworkers. According to this concept, adverse events at a critical period of development induce long-lasting consequences. Classically, undernourished fetuses adapt to a limited placental nutrient supply to ensure survival but at the expenses of cardiovascular, hormonal, and metabolic reactions that manifest as diseases in adult life. These complex adaptive processes are designated as programming [76,77]. Among early, well-defined pathogenetic factors, increased salt intake emerged as an important player mediating the increased risk of cardiovascular diseases in adults.

In support of this notion, a prenatal high-salt diet in Sprague–Dawly rats has been shown to program blood pressure and heart rate hyperresponsiveness in adult female offspring [78]. Moreover, the adverse effects of excessive sodium intake during pregnancy on the vascular structure of adult offspring have been documented by demonstrating a thicker wall of central arteries, collagen deposition, smooth muscle cell proliferation, and an increased expression of the OS marker, nitrothyrosine [79,80]. The oxidative damage of the vascular wall has been claimed to be accounted for by high levels of circulating cardiotonic steroid marinobufagenin (MBG), which is known to mediate the production of superoxide and peroxynitrite via NADPH oxidase activation [81]. In addition to elevated MBG levels, a reduced expression of eNOS and the NO receptor, soluble guanylate cyclase, with a concomitant increase of circulating ADMA, the competitive inhibitor of NOS, was observed [82]. Elevated asymmetric dimethylarginine (ADMA) levels may be due to redox-sensitive enzyme reactions as its generation by protein methyltransferase (PRMT) is enhanced while its elimination by dimethylarginine dimethylaminohydrolase (DDAH) is inhibited by ROS. In this regard, it should be considered that group described a markedly elevated plasma ADMA level of premature infants during the first weeks of life and assumed its contribution to the development of cardiovascular diseases in adulthood [83]. Similarly, urinary excretion of endogenous ouabain (EOLS), as a marker of its adrenal secretion, proved to be higher in healthy preterm infants as compared to full-term neonates and remained elevated during the study period of five weeks. When supplemental sodium was given to the preterm infants, urinary EOLS decreased significantly. It was postulated, therefore, that EOLS appears to be regulated by the excessively activated renin-angiotensin stimulation in the nonsupplemented, sodium- and volume-depleted group rather than the volume status of the supplemented groups of preterm neonates [84]. It may also be relevant to note that EOLS proved to be an independent predictor of impaired diurnal blood pressure rhythm and arterial stiffness in adult patients with subclinical organ damage in treated hypertensive patients [85].

In a cross-sectional study of 569 pregnant women from the Odense Child Cohort, urinary sodium and potassium excretion with plasma levels and urinary aldosterone excretion were measured at 29 weeks of gestation to assess their predictive value of feto-placental development and preeclampsia. Salt intake of more than 6 g/kg proved to be an independent predictor of preeclampsia and pregnancy-induced hypertension whereas aldosterone was significantly associated with placental weight and birth weight. Based on these results, it was concluded that high sodium combined with low potassium intake directly increase the risk of preeclampsia. Indirectly, however, suppressing aldosterone production impairs feto-placental development via reducing VEGF and placental growth factor expression ^[3]. The protective effects of aldosterone on the function of the feto-placental unit have already been established by others ^[4][5].

In a recent comprehensive review, Scaife and Hohaupt carefully evaluated the association of preeclampsia, salt intake, and aldosterone production and provided evidence that the placenta, similar to the skin interstitium, functions as a salt-sensitive organ and regulates sodium balance ^[6]. Indeed, the negatively charged GAGa and proteoglycans (syndecan 2, glycopicans 1,3, decorin, perlecan) are abundantly expressed in the placenta of healthy pregnancy and bind and reversibly store excess sodium ^[7][8]. Accumulated sodium generates hypertonicity that induces macrophage invasion and activation. Activated macrophages release TonEBP and VEGF-C, leading to lymphangiogenesis and eNOS expression. This sodium reservoir can buffer excess sodium and maintain low vascular resistance and utero-placental perfusion. In preeclampsia, the capacity of this system is markedly reduced and cannot meet the actual sodium (and volume) requirements of utero-placental circulation. It is suggested, therefore, that supplemental NaCl should be provided to reestablish normal plasma volume to compensate for the low aldosterone characteristic of preeclampsia. NaCl supplementation had also been claimed to alter immune milieu by preventing a decrease of CD14 macrophages and the unfavourable cytokine balance that may lead to defective placentation ^[9].

It should be noted that increased levels of tissue sodium have been shown to enhance the polarization of naïve Th cells to Th17 cells, and via their IL 17 production, they may increase the generation of ROS and proinflammatory cytokines that may limit NO bioavailability ^[10]. These untoward effects of sodium accumulation in the placental tissue are certainly overcome by the benefit of the activation of TonEBP-VEGF-C-eNOS pathways ^[11].

2. Prenatal High Sodium Intake and Vascular Programming

The concept of the developmental origin of certain chronic diseases in adulthood was conceived by Barker and coworkers. According to this concept, adverse events at a critical period of development induce long-lasting consequences. Classically, undernourished fetuses adapt to a limited placental nutrient supply to ensure survival but at the expenses of cardiovascular, hormonal, and metabolic reactions that manifest as diseases in adult life. These complex adaptive processes are designated as programming ^[12][13]. Among early, well-defined pathogenetic factors, increased salt intake emerged as an important player mediating the increased risk of cardiovascular diseases in adults.

In support of this notion, a prenatal high-salt diet in Sprague–Dawly rats has been shown to program blood pressure and heart rate hyperresponsiveness in adult female offspring ^[14]. Moreover, the adverse effects of excessive sodium intake during pregnancy on the vascular structure of adult offspring have been documented by demonstrating a thicker wall of central arteries, collagen deposition, smooth muscle cell proliferation, and an increased expression of the OS marker, nitrothyrosine ^[15][16]. The oxidative damage of the vascular wall has been claimed to be accounted for by high levels of circulating cardiotonic steroid marinobufagenin (MBG), which is known to mediate the production of superoxide and peroxynitrite via NADPH oxidase activation ^[17]. In addition to elevated MBG levels, a reduced expression of eNOS and the NO receptor, soluble guanylate cyclase, with a concomitant increase of circulating ADMA, the competitive inhibitor of NOS, was observed ^[18]. Elevated asymmetric dimethylarginine (ADMA) levels may be due to redox-sensitive enzyme reactions as its generation by protein methyltransferase (PRMT) is enhanced while its elimination by dimethylarginine dimethylaminohydrolase (DDAH) is inhibited by ROS. In this regard, it should be considered that group described a markedly elevated plasma ADMA level of premature infants during the first weeks of life and assumed its contribution to the development of cardiovascular diseases in adulthood ^[19]. Similarly, urinary excretion of endogenous ouabain (EOLS), as a marker of its adrenal secretion, proved to be higher in healthy preterm infants as compared to full-term neonates and remained elevated during the study period of five weeks. When supplemental sodium was given to the preterm infants, urinary EOLS decreased significantly. It was postulated, therefore, that EOLS appears to be regulated by the excessively activated renin-angiotensin stimulation in the nonsupplemented, sodium- and volume-depleted group rather than the volume status of the supplemented groups of preterm neonates ^[20]. It may also be relevant to note that EOLS proved to be an independent predictor of impaired diurnal blood pressure rhythm and arterial stiffness in adult patients with subclinical organ damage in treated hypertensive patients ^[21].

3. Perinatal Adaptation and Oxidative Stress

In a most recent review, Lembo et al. have summarized the most important aspects of the current knowledge on the impact of OS on the perinatal adaptation of preterm neonates ^[22]. It has been clearly shown that the generation of AFR exceeds the capacity of enzymatic and nonenzymatic antioxidant defense mechanisms during the perinatal period. Therefore, an imbalance develops between the pro- and antioxidant systems, which is designated as OS. Prenatally, reactive oxygen species (ROS) generation is mainly due to the fetal inflammatory response syndrome that comprises infection, hypoxia, and ischemia-reperfusion ^[23]. In the postnatal care respiratory support, instable circulation, parenteral nutrition, and fluid therapy should be considered as a source of ROS generation. ROS may cause cellular, tissue, and organ damage and induce the so-called free radical-mediated pathologies (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular haemorrhage, respiratory distress syndrome, and patent ductus arteriosus). Importantly, the association of fluid intake and cardiopulmonary adaptation has been widely studied, and it consistently demonstrated that high, versus restricted, fluid intake negatively influenced these complex processes ^{[24][25][26][27]}. To our knowledge, only one study has been performed to address the impact of sodium supplementation, independent of fluid intake, on the cardiopulmonary adaptation. In this randomized, controlled clinical trial, the effects of early (on the second day) and late (when 6% of birth weight was lost) sodium supplementation (4 mmol/kg) were compared on oxygen dependency and body weight in preterm infants with a gestational age of 25–30 weeks. Clinical variables, including fluid and energy intake, were comparable. Preterm infants receiving early sodium supplements needed more respiratory support both on postnatal day 6, and on day 28, but their weight curves and plasma sodium concentrations were similar ^[28]. The authors did not provide a clear explanation for the more compromised cardiopulmonary adaptation in the early supplemented group, but others suggested that the excess sodium may cause excess volume that is responsible for the respiratory compromise ^[25].

3. Perinatal Adaptation and Oxidative Stress

In a most recent review, Lembo et al. have summarized the most important aspects of the current knowledge on the impact of OS on the perinatal adaptation of preterm neonates [86]. It has been clearly shown that the generation of AFR exceeds the capacity of enzymatic and nonenzymatic antioxidant defense mechanisms during the perinatal period. Therefore, an imbalance develops between the pro- and antioxidant systems, which is designated as OS. Prenatally, reactive oxygen species (ROS) generation is mainly due to the fetal inflammatory response syndrome that comprises infection, hypoxia, and ischemia-reperfusion [87]. In the postnatal care respiratory support, instable circulation, parenteral nutrition, and fluid therapy should be considered as a source of ROS generation. ROS may cause cellular, tissue, and organ damage and induce the so-called free radical-mediated pathologies (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular haemorrhage, respiratory distress syndrome, and patent ductus arteriosus). Importantly, the association of fluid intake and cardiopulmonary adaptation has been widely studied, and it consistently demonstrated that high, versus restricted, fluid intake negatively influenced these complex processes [88,89,90,91]. To our knowledge, only one study has been performed to address the impact of sodium supplementation, independent of fluid intake, on the cardiopulmonary adaptation. In this randomized, controlled clinical trial, the effects of early (on the second day) and late (when 6% of birth weight was lost) sodium supplementation (4 mmol/kg) were compared on oxygen dependency and body weight in preterm infants with a gestational age of 25–30 weeks. Clinical variables, including fluid and energy intake, were comparable. Preterm infants receiving early sodium supplements needed more respiratory support both on postnatal day 6, and on day 28, but their weight curves and plasma sodium concentrations were similar [92]. The authors did not provide a clear explanation for the more compromised cardiopulmonary adaptation in the early supplemented group, but others suggested that the excess sodium may cause excess volume that is responsible for the respiratory compromise [89].