Neonates with Bartter syndrome have enormous fluid and sodium requirements.

AIM: Managing neonatal Bartter syndrome by achieving adequate weight gain is challenging. We assessed the correlation between weight gain in neonatal Bartter syndrome and the introduction of fluid and sodium supplementations and indomethacin during the first 4 weeks of life. METHODS: Daily fluid and electrolytes requirements were analysed using linear regression and Spearman correlation coefficients. The weight gain coefficient was calculated as daily weight gain after physiological neonatal weight loss. RESULTS: We studied seven infants. The highest weight gain coefficients occurred between weeks two and four in the five neonates who either received prompt amounts of fluid (maximum 810 mL/kg/day) and sodium (maximum 70 mmol/kg/day) or were treated with indomethacin. For the two patients with the highest weight gain coefficient, water and sodium supplementations were decreased in weeks two to four leading to a significant negative Spearman correlation between weight gain and fluid supplements (r = -0.55 and -0.68) and weight gain and sodium supplementations (r = -0.96 and -0.72). The two patients with the lowest weight gain coefficient had positive Spearman correlation coefficients between weight gain and fluid and sodium supplementations. CONCLUSION: Infants with neonatal Bartter syndrome required rapid and enormous fluid and sodium supplementations or the early introduction of indomethacin treatment to achieve adequate weight gain during the early postnatal period.

Epithelial Sodium Channel-Mediated Sodium Transport Is Not Dependent on the Membrane-Bound Serine Protease CAP2/Tmprss4.

The membrane-bound serine protease CAP2/Tmprss4 has been previously identified in vitro as a positive regulator of the epithelial sodium channel (ENaC). To study its in vivo implication in ENaC-mediated sodium absorption, we generated a knockout mouse model for CAP2/Tmprss4. Mice deficient in CAP2/Tmprss4 were viable, fertile, and did not show any obvious histological abnormalities. Unexpectedly, when challenged with sodium-deficient diet, these mice did not develop any impairment in renal sodium handling as evidenced by normal plasma and urinary sodium and potassium electrolytes, as well as normal aldosterone levels. Despite minor alterations in ENaC mRNA expression, we found no evidence for altered proteolytic cleavage of ENaC subunits. In consequence, ENaC activity, as monitored by the amiloride-sensitive rectal potential difference (ΔPD), was not altered even under dietary sodium restriction. In summary, ENaC-mediated sodium balance is not affected by lack of CAP2/Tmprss4 expression and thus, does not seem to directly control ENaC expression and activity in vivo.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

The role of the renal mineralocorticoid versus the glucocorticoid receptor in renal sodium and potassium transport

Dans le néphron distal sensible à l'aldostérone, le récepteur aux minéralocorticoïdes (RM) et le récepteur aux glucocorticoids (RG) sont exprimés et peuvent être liés et activés par l'aldostérone et le Cortisol, respectivement. La réabsorption rénale de sodium est principalement contrôlée par le RM. Cependant, des modèles expérimentaux in vitro et in vivo suggèrent que le RG pourrait également jouer un rôle dans le transport rénal du sodium. Afin d'étudier l'implication du RG et/ou du RM exprimés dans les cellules épithéliales adultes dans le transport rénal du sodium, nous avons généré deux modèles de souris, dans lesquelles l'expression du RG (Nr3c1Pax8/LC1) ou du RM (Nr3c2Pax8/LC1) peut être abolie de manière inductible et cela spécifiquement dans les tubules rénaux. Les souris déficientes pour le gène du RM survivent mais développent un phénotype sévère de PHA-1, caractérisé par un retard de croissance, une augmentation des niveaux urinaires de Na+, une diminution de la concentration du Na+ dans le plasma, une hyperkaliémie et une augmentation des niveaux d'aldostérone plasmatique. Ce phénotype empire et devient létal lorsque les souris sont nourries avec une diète déficiente en sodium. Les niveaux d'expression en protéine de NCC, de la forme phosphorylée de NCC et de aENaC sont diminués, alors que l'expression en ARN messager et en protéine du RG est augmentée. Une diète riche en Na+ et pauvre en K+ ne corrige pas la concentration élevée d'aldostérone dans le plasma pour la ramener à des niveaux conformes, mais est suffisante pour corriger la perte de poids et les niveaux anormaux des électrolytes dans le plasma et l'urine. -- In the aldosterone-sensitive distal nephron, both the mineralocorticoid (MR) and the glucocorticoid (GR) receptor are expressed. They can be bound and activated by aldosterone and Cortisol, respectively. Renal Na+ reabsorption is mainly controlled by MR. However, in vitro and in vivo experimental models suggest that GR may play a role in renal Na+ transport. Therefore, to investigate the implication of MR and/or GR in adult epithelial cells in renal sodium transport, we generated inducible renal tubule- specific MR (Nr3c2Pax8/LC1) and GR (Nr3c1Pax8/LC1) knockout mice. MR-deficient mice survived but developed a severe PHA-1 phenotype with failure to thrive, higher urinary Na+, decreased plasma Na+ levels, hyperkalemia and higher levels of plasma aldosterone. This phenotype further worsened and became lethal under a sodium-deficient diet. NCC protein expression and its phosphorylated form, as well as aENaC protein level were downregulated, whereas the mRNA and protein expression of GR was increased. A diet rich in Na+and low in K+ did not normalize plasma aldosterone to control levels, but was sufficient to restore body weight, plasma and urinary electrolytes. Upon switch to a Na+-deficient diet, GR-mutant mice exhibited transient increased urinary Na+ and decreased K+ levels, with transitory higher plasma K+ concentration preceded by a significant increase in plasma aldosterone levels within the 12 hours following diet switch. We found no difference in urinary aldosterone levels, plasma Na+ concentration and plasma corticosterone levels. Moreover, NHE3, NKCC2, NCC

Sodium-dependent phosphate transporters in osteoclast differentiation and function.

Osteoclasts are multinucleated bone degrading cells. Phosphate is an important constituent of mineralized bone and released in significant quantities during bone resorption. Molecular contributors to phosphate transport during the resorptive activity of osteoclasts have been controversially discussed. This study aimed at deciphering the role of sodium-dependent phosphate transporters during osteoclast differentiation and bone resorption. Our studies reveal RANKL-induced differential expression of sodium-dependent phosphate transport protein IIa (NaPi-IIa) transcript and protein during osteoclast development, but no expression of the closely related NaPi-IIb and NaPi-IIc SLC34 family isoforms. In vitro studies employing NaPi-IIa-deficient osteoclast precursors and mature osteoclasts reveal that NaPi-IIa is dispensable for bone resorption and osteoclast differentiation. These results are supported by the analysis of structural bone parameters by high-resolution microcomputed tomography that yielded no differences between adult NaPi-IIa WT and KO mice. By contrast, both type III sodium-dependent phosphate transporters Pit-1 and Pit-2 were abundantly expressed throughout osteoclast differentiation, indicating that they are the relevant sodium-dependent phosphate transporters in osteoclasts and osteoclast precursors. We conclude that phosphate transporters of the SLC34 family have no role in osteoclast differentiation and function and propose that Pit-dependent phosphate transport could be pivotal for bone resorption and should be addressed in further studies.