Abnormal neonatal sodium handling in skin precedes hypertension in the SAME rat

We discovered high Na(+) and water content in the skin of newborn Sprague-Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2(-/-) animals exhibiting lower skin Na(+) and water levels than controls at birth, they retained ~ 30% higher Na(+) content in their pelts at the expense of K(+) thereafter. Hsd11b2(-/-) neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na(+) through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na(+) imbalance in the Hsd11b2(-/-) neonate leads to excess Na(+) storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na(+) uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na(+) plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney

HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

Infection and inflammation are able to induce diet-independent Na+-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na+-boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na+ (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na+- modulated cell autonomous innate immunity.This work was supported by the Deutsche Forschungsgemeinschaft [WA 2539/4-1, 5-1, 7-1]; Deutsche Forschungsgemeinschaft (DE) [JA 1993/ 4-1]; Universitätsklinikum Regensburg [Reform C]; NIHR Cambridge Blood and Transplant Research Unit Organ Donation

Pathological Importance of the Endothelin-1/ETB Receptor System on Vascular Diseases

Activation of the endothelin (ET)-1/ET receptor system is involved in the development of vascular diseases such as atherosclerosis, vascular hypertrophy, and restenosis. Some issues still remain unresolved including whether ET receptor antagonists are expected to become the new therapeutic tools for the treatment of vascular diseases. One of the unresolved critical points is the functional role of ET receptor subtypes on each vascular disease, in particular the pathophysiological roles of the ETB receptor. We recently demonstrated that selective inhibition of the ETB receptor system showed harmful effects in the development of neointimal formation after vascular injury. However, there was no apparent difference in the therapeutic effects between a nonselective ETA/ETB receptor antagonist and selective ETA receptor antagonist. These findings indicate that antagonism of the ETA receptor system is essential for suppressing vascular remodeling, irrespective of the presence of ETB-receptor-mediated actions, although the selective ETB receptor antagonist worsens vascular remodeling. In addition, we found that ET receptor systems contribute to sex differences in the severity of vascular disease, thereby suggesting that the efficacy of ET receptor antagonists for vascular diseases may differ between sexes. In this paper, we outline the roles of the ET-1/ETB receptor system on vascular diseases and its sex differences

Oxidative stress-induced glomerular mineralocorticoid receptor activation limits the benefit of salt reduction in Dahl salt-sensitive rats

Background Mineralocorticoid receptor (MR) antagonists attenuate renal injury in salt-sensitive hypertensive rats with low plasma aldosterone levels. We hypothesized that oxidative stress causes MR activation in high-salt-fed Dahl salt-sensitive rats. Furthermore, we determined if MR activation persisted and induced renal injury, even after switching from a high- to a normal-salt diet.Methods and Findings High-salt feeding for 4 weeks increased dihydroethidium fluorescence (DHE, an oxidant production marker), p22phox (a NADPH oxidase subunit) and serum and glucocorticoid-regulated kinase-1 (SGK1, an MR transcript) in glomeruli, compared with normal-salt feeding, and these changes persisted 4 weeks after salt withdrawal. Tempol treatment (0.5 mmol/L) during high-salt feeding abolished the changes in DHE fluorescence, p22phox and SGK1. Dietary salt reduction after a 4-week high-salt diet decreased both blood pressure and proteinuria, but was associated with significantly higher proteinuria than in normal control rats at 4 weeks after salt reduction. Administration of tempol during high-salt feeding, or eplerenone, an MR antagonist (100 mg/kg/day), started after salt reduction, recovered proteinuria to normal levels at 4 weeks after salt reduction. Paraquat, a reactive oxygen species generator, enhanced MR transcriptional activity in cultured rat mesangial cells and mouse podocytes.Conclusions These results suggest that oxidative stress plays an important role in glomerular MR activation in Dahl salt-sensitive rats. Persistent MR activation even after reducing salt intake could limit the beneficial effects of salt restriction