Glycine protects against hepatocyte killing by KCN or hypoxia by preventing intracellular Na+ overload in the rat

Abstract

exposed to endotoxin shock. 7 Although the cytoprotective Glycine has been shown to prevent hepatocyte death ineffect of glycine is well established, the mechanisms involved duced by anoxia and by several toxic agents. However, the still must be fully clarified. Cytoprotection by glycine, in fact, mechanisms responsible for such a cytoprotective effect have is not related to the preservation of intracellular ATP, nor not yet been entirely clarified. We have previously shown that does it require protein synthesis or mitochondrial metaboan uncontrolled increase in intracellular Na / is critical for lism of the amino acid. 1,3 Moreover, glycine does not prevent hepatocyte killing induced by adenosine triphosphate (ATP) intracellular acidification consequent to ATP depletion, 3,8 depletion. We herein report that protection by glycine (2 and it does not interfere with the accumulation of unesterimmol/L) against cytotoxicity induced in isolated rat hepatofied fatty acids in isolated renal proximal tubular cells. 9 Recyte by potassium cyanide (KCN) or hypoxia was associated cently, glycine has been shown to inhibit nonlysosomal prowith the prevention of cytosolic Na / accumulation. The additeolysis in rat hepatocytes exposed to potassium cyanide tion of the Na / ionophore, monensin, abolished the effects of (KCN) or anoxia, suggesting that it might protect against glycine on both Na / increase and cytotoxicity. Pretreating hepatocellular injury by preventing the activation of degradahepatocytes with the glycine-receptor antagonist, strychnine tive proteolytic processes. the intracellular acidification consequent to mitochondrial dysfunctions, whereas the block of Na / efflux is mainly The small, neutral amino acid, glycine, has been shown to caused by the inhibition of the Na / /K / ATPase activity conseprevent irreversible cell injury caused by adenosine triphosquent to ATP depletion. 16 Consistently, the incubation of phate (ATP) depletion in rabbit renal proximal tubular isolated hepatocytes in a bicarbonate-free buffer or in an cells, 1,2 rat hepatocytes, 3,4 and human endothelial cells. 5 acidic medium (pH 6.5) greatly reduced Na / overload and Moreover, glycine addition minimizes reperfusion injury of cell killing by the redox cycling agent, menadione, 16 which is rat liver in a low-flow/reflow liver perfusion model, 6 while known to damage mitochondria and cause ATP depletion.12 feeding a glycine-containing diet improves the survival of rat These observations have prompted us to investigate whether the cytoprotective activity of glycine against the hepatotoxic action of anoxia or KCN poisoning might be asAbbreviations: ATP, adenosine triphosphate; KCN, potassium cyanide; NPPB, 5-cribed to an effect on Na / accumulation.nitro-2-(3-phenylpropylamino) benzoic acid.

Salmonella Rapidly Kill Dendritic Cells via a Caspase-1- Dependent Mechanism

“…5C), the linear increase of which suggests that Salmonella may inflict constant but permanent damage to the dendritic cell plasma membrane. To test this hypothesis, dendritic cells were pretreated with glycine, which inhibits necrotic cell death by blocking nonspecific ion fluxes across the plasma membrane (33)(34)(35)(36). In agreement with recent evidence that glycine can inhibit bacterially induced host cell death (15,37), Salmonella-induced cytotoxicity to both caspase-1 ϩ/Ϫ and caspase-1 Ϫ/Ϫ dendritic cells was dramatically reduced in the presence of exogenous glycine (Fig.…”

Ischemic preconditioning reduces Na+ accumulation and cell killing in isolated rat hepatocytes exposed to hypoxia

“…12,16 Furthermore, conditions that prevented Na ϩ overload were found to be protective against the cytotoxic effects of hypoxia, mitochondrial damage, or oxidative stress. 12,17 The measurement of intracellular Na ϩ levels during hypoxic incubation showed a significant reduction of Na ϩ accumulation in preconditioned hepatocytes compared with nonpreconditioned cells (Fig. 2).…”

Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide

“…29 In these conditions, Na ϩ overload is the result of the activation of Na ϩ /H ϩ exchanger and Na ϩ /HCO 3 Ϫ cotransporter in response to intracellular acidosis combined with the impairment of Na ϩ extrusion by Na ϩ /K ϩ -adenosine triphosphatase. 14 Conditions that reduce Na ϩ influx, such as cell incubation in the absence of extracellular Na ϩ , 14,29 addition of glycine, 30 or inhibition of Na ϩ /H ϩ exchanger, 14 all prevent the cell killing. Moreover, by activating PKC-␦ and p38 MAPK, hypoxic preconditioning reduces hepatocyte Na ϩ overload.…”