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Synthesis of ophthalmic acid in liver and kidney in vivo.

ABSTRACT: The synthesis of ophthalmic acid, an analogue of glutathione, was studied in vivo in mouse liver and kidney after administration of either L-alpha-aminobutyrate or L-gamma-glutamyl-L-alpha-aminobutyrate as precursor. L-alpha-aminobutyrate accumulated to a much greater extent, and induced a much greater synthesis of ophthalmic acid in the liver than in the kidney. In contrast, L-gamma-glutamyl-L-alpha-aminobutyrate initiated a large and more rapid synthesis of ophthalmic acid in the kidney than in the liver. Experiments with L-gamma-[G(-14)C]glutamyl-L-alpha-aminobutyrate showed that, although part of the dipeptide is degraded to its constituent amino acids, a significant proportion is directly incorporated into kidney ophthalmic acid. In contrast L-gamma-glutamyl-L-alpha-aminobutyrate serves poorly as a direct precursor of liver ophthalmic acid. The present results show that kidney gamma-glutamyl tripeptide synthesis can proceed directly from an exogenous gamma-glutamyl dipeptide precursor.

SUBMITTER: Orlowski M

PROVIDER: S-EPMC1183909 | biostudies-other | 1978 Feb

REPOSITORIES: biostudies-other

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Project description:With limited therapeutic intervention in preventing the progression to end-stage renal disease, chronic kidney disease (CKD) remains a global health-care burden. Aristolochic acid (AA) induced nephropathy is a model of CKD characterised by inflammation, tubular injury, and interstitial fibrosis. Human liver stem cell-derived extracellular vesicles (HLSC-EVs) have been reported to exhibit therapeutic properties in various disease models including acute kidney injury. In the present study, we aimed to investigate the effects of HLSC-EVs on tubular regeneration and interstitial fibrosis in an AA-induced mouse model of CKD. NSG mice were injected with HLSC-EVs 3 days after administering AA on a weekly basis for 4 weeks. Mice injected with AA significantly lost weight over the 4-week period. Deterioration in kidney function was also observed. Histology was performed to evaluate tubular necrosis, interstitial fibrosis, as well as infiltration of inflammatory cells/fibroblasts. Kidneys were also subjected to gene array analyses to evaluate regulation of microRNAs (miRNAs) and pro-fibrotic genes. The effect of HLSC-EVs was also tested in vitro to assess pro-fibrotic gene regulation in fibroblasts cocultured with AA pretreated tubular epithelial cells. Histological analyses showed that treatment with HLSC-EVs significantly reduced tubular necrosis, interstitial fibrosis, infiltration of CD45 cells and fibroblasts, which were all elevated during AA induced injury. At a molecular level, HLSC-EVs significantly inhibited the upregulation of the pro-fibrotic genes α-Sma, Tgfb1, and Col1a1 in vivo and in vitro. Fibrosis gene array analyses revealed an upregulation of 35 pro-fibrotic genes in AA injured mice. Treatment with HLSC-EVs downregulated 14 pro-fibrotic genes in total, out of which, 5 were upregulated in mice injured with AA. Analyses of the total mouse miRnome identified several miRNAs involved in the regulation of fibrotic pathways, which were found to be modulated post-treatment with HLSC-EVs. These results indicate that HLSC-EVs play a regenerative role in CKD possibly through the regulation of genes and miRNAs that are activated during the progression of the disease.

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Synthesis of ophthalmic acid in liver and kidney in vivo.

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