Abstract. Aldosterone exerts its effects through interactions with two types of binding sites, the mineralocorticoid (MR) and the glucocorticoid (GR) receptors. Although both receptors are known to be involved in the anti-natriuretic response to aldosterone, the mechanisms of signal transduction leading to modulation of electrolyte transport are not yet fully understood. This study measured the Na ϩ and K ϩ urinary excretion and the mRNA levels of three known aldosterone-induced transcripts, the serum and glucocorticoid-induced kinase (Sgk-1), the ␣ subunit of the epithelial Na ϩ channel (␣ENaC), and the glucocorticoid-induced-leucine-zipper protein (GILZ) in the whole kidney and in isolated cortical collecting tubules of adrenalectomized rats treated with low doses of aldosterone and/or dexamethasone. The resulting plasma concentrations of both steroids were close to 1 nmol/L. Aldosterone, given with or without dexamethasone, induced anti-natriuresis and kaliuresis, whereas dexamethasone alone did not. GILZ and ␣ENaC transcripts were higher after treatment with either or both hormones, whereas the mRNA abundance of Sgk-1 was increased in the cortical collecting tubule by aldosterone but not by dexamethasone. We conclude the increased expression of Sgk-1 in the cortical collecting tubules is a primary event in the early antinatriuretic and kaliuretic responses to physiologic concentrations of aldosterone. Induction of ␣ENaC and/or GILZ mRNAs may play a permissive role in the enhancement of the early and/or late responses; these effects may be necessary for a full response but do not by themselves promote early changes in urinary Na ϩ and K ϩ excretion.
Impairment of the blood–brain barrier (BBB) integrity is implicated in the numerous neurological disorders associated with neuroinflammation, neurodegeneration and aging. It is now evident that short-chain fatty acids (SCFAs), mainly acetate, butyrate and propionate, produced by anaerobic bacterial fermentation of the dietary fiber in the intestine, have a key role in the communication between the gastrointestinal tract and nervous system and are critically important for the preservation of the BBB integrity under different pathological conditions. The effect of SCFAs on the improvement of the compromised BBB is mainly based on the decrease in paracellular permeability via restoration of junctional complex proteins affecting their transcription, intercellular localization or proteolytic degradation. This review is focused on the revealed and putative underlying mechanisms of the direct and indirect effects of SCFAs on the improvement of the barrier function of brain endothelial cells. We consider G-protein-coupled receptor-mediated effects of SCFAs, SCFAs-stimulated acetylation of histone and non-histone proteins via inhibition of histone deacetylases, and crosstalk of these signaling pathways with transcriptional factors NF-κB and Nrf2 as mainstream mechanisms of SCFA’s effect on the preservation of the BBB integrity.
Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, is the most abundant proinflammatory agent. Considerable evidence indicates that LPS challenge inescapably causes oxidative stress and mitochondrial dysfunction, leading to cell and tissue damage. Increased mitochondrial reactive oxygen species (mtROS) generation triggered by LPS is known to play a key role in the progression of the inflammatory response. mtROS at excessive levels impair electron transport chain functioning, reduce the mitochondrial membrane potential, and initiate lipid peroxidation and oxidative damage of mitochondrial proteins and mtDNA. Over the past 20 years, a large number of mitochondria-targeted antioxidants (mito-AOX) of different structures that can accumulate inside mitochondria and scavenge free radicals have been synthesized. Their protective role based on the prevention of oxidative stress and the restoration of mitochondrial function has been demonstrated in a variety of common diseases and pathological states. This paper reviews the current data on the beneficial application of different mito-AOX in animal endotoxemia models, in either in vivo or in vitro experiments. The results presented in our review demonstrate the promising potential of approaches based on mito-AOX in the development of new treatment strategies against Gram-negative infections and LPS per se.
BACKGROUND AND PURPOSEcGMP is involved in the regulation of many cellular processes including cardiac and smooth muscle contractility, aldosterone synthesis and inhibition of platelet activation. Intracellular effects cGMP are mediated by cGMP-dependent PKs, cGMPregulated PDEs and cGMP-gated ion channels. PKG inhibitors are widely used to discriminate PKG-specific effects. They can be divided into cyclic nucleotide-binding site inhibitors such as Rp-phosphorothioate analogues (Rp-cGMPS), ATP-binding site inhibitors such as KT5823, and substrate binding site inhibitors represented by the recently described DT-oligopeptides. As it has been shown that Rp-cGMPS and KT5823 have numerous non-specific effects, we analysed the pharmacological properties of the oligopeptide (D)-DT-2 described as a highly specific, membrane-permeable, PKG inhibitor. EXPERIMENTAL APPROACHSpecificity and potency of (D)-DT-2 to inhibit PKG activity was evaluated using biochemical assays in vitro and by substrate phosphorylation analysis in various cell types including human platelets, rat mesangial cells and rat neonatal cardiomyocytes. KEY RESULTSDespite potent inhibition of PKGI in vitro, (D)-DT-2 lost specificity for PKG in cell homogenates and particularly in living cells, as demonstrated by phosphorylation of different substrates. Instead, (D)-DT-2 modulated activity of other kinases including ERK, p38, PKB and PKC, thereby inducing unpredicted and often opposing functional effects. CONCLUSIONS AND IMPLICATIONSWe conclude that DT-oligopeptides, as other inhibitors, cannot be used to specifically inhibit PKG in intact cells. Therefore, no specific pharmacological PKG inhibitors are available, and reliable studies of PKG signalling can only be made by using RNA knockdown or genetic deletion methods. AbbreviationsANP, atrial natriuretic peptide; GC-A receptor, guanylyl cyclase-A receptor; NRVM, neonatal rat ventricular myocytes; RMC, rat mesangial cells; SNP, sodium nitroprusside; VASP, vasodilator-stimulated phosphoprotein.
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