PubMed · 386719
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J B Walker. 1979. Creatine: biosynthesis, regulation, and function.. https://doi.org/10.1002/9780470122952.ch4
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The incidence of drug-induced nephrotoxicity (DIN) has recently been increasing. Based on developments in molecular biology and cell biology, cultured cells have become a very useful tool for investigating DIN. Especially, the immortalized cell lines derived from well-defined nephron segments are ideal for such studies. As indicators to detect DIN, myosin light chain phosphorylation in glomerular mesangial cells, enzymes of proximal tubule origin such as glycine-amidinotransferase, cytosolic free calcium concentration and intracellular ATP content may be useful. The involvement of nitric oxide and heat shock protein in DIN has been reported. Therapeutic effects of growth factors such as HGF or EGF for DIN have been identified. The direct evidence for the involvement of reactive oxygen species and the molecular basis for redox regulation in DIN is required. Cisplatin has been shown to induce apoptosis, and the role of apoptosis in DIN remains to be further clarified. Thus, in parallel with in vivo studies, cultured cells provide an opportunity for clarifying the intracellular mechanism for DIN more precisely and establishing an efficient screening system to develop drugs to prevent DIN.
L-Arginine:glycine amidinotransferase (transamidinase) occurs at high concentrations in the kidney and the pancreas of rats. The cellular localization of transamidinase was investigated in fetal, neonatal, and adult rat pancreatic tissue using three indicators of the presence of transamidinase: (1) immunofluorescence microscopy, (2) in vitro enzymatic activity measurements on homogenates of whole pancreas and on isolated acinar and islet tissue from adult rats, and (3) ornithine production from perfused adult rat pancreas. The cellular localization of transamidinase was determined in fetal, neonatal, and adult rat pancreas, using a polyclonal guinea pig antibody made against a highly purified preparation of kidney transamidinase. Immunoreactive transamidinase was detected only in the pancreatic acinar cells. The cellular distribution of the immunostaining was compatible with the presence of transamidinase in mitochondria. The transamidinase enzymatic activity of whole pancreatic homogenates was 13.4 +/- 0.7 U/g wet weight (n = 11). In pancreata where islets had been isolated away from the acinar tissue, the transamidinase activity was similar to that of the whole pancreatic homogenates (16.8 +/- 2 U/g wet weight). Any transamidinase activity present in isolated islets was below the sensitivity of the assay. Transamidinase activity in the isolated perfused pancreas was determined by measuring the amount of ornithine released into the perfusate. The transamidinase activity of the perfused pancreas was 16.4 +/- 1.8 U/g pancreas and is an estimate of the physiological production capacity of the enzyme (270 +/- 29 nmol ornithine/min/g pancreas). These results indicate that transamidinase is present at high concentrations in the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)
L-Arginine-glycine amidinotransferase (transamidinase) is the first and rate-limiting step in creatine biosynthesis. Rats fed a creatine-supplemented diet or hypophysectomized rats have only 20% of the kidney transamidinase activity as intact rats fed a creatine-free diet. A cDNA clone corresponding to transamidinase was isolated by immunoscreening of a lambda gt11 expression library prepared from rat kidney mRNA. The transamidinase cDNA had an open reading frame containing the known sequence of the amino-terminal peptide of transamidinase. Based on the cDNA sequence, transamidinase is synthesized as a precursor with an amino-terminal extension of 50 amino acids, consistent with its mitochondrial localization. Comparison of the transamidinase sequence with the protein data base identified only a single, related protein. Remarkably, this protein, which has a 37% amino acid identity with transamidinase, is also an amidinotransferase, catalyzing streptomycin biosynthesis in Streptomyces griseus. Transamidinase cDNA was used to investigate the regulation of mRNA levels by creatine and growth hormone. Hypophysectomized rats were fed a creatine-free or a creatine-supplemented diet and maintained with and without injections of growth hormone. An excellent correlation was found between changes in transamidinase activity and mRNA levels in response to creatine and growth hormone. Thus, the regulation of transamidinase by creatine and growth hormone is at a pretranslational level. In addition, the two effectors do not act independently but interact at a pretranslational level to control transamidinase gene expression.