Biosynthesis of Guanidinoacetic Acid in Isolated Renal Tubules

Takeda, Michio; Kiyatake, Ikuo; Koide, Hikaru; Jung, Kyu Yong; Endou, Hitoshi

doi:10.1515/cclm.1992.30.6.325

Cited by 22 publications

(27 citation statements)

References 30 publications

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“…We already showed that this process is very sensitive to circulating citrulline concentration in the rat (9). Renal arginine synthesis occurs in the cells of the proximal tubule (10) as does GAA synthesis (13,22). Therefore, arginine synthesized in these cells becomes immediately available as a substrate for GAA synthesis.…”

Section: Discussionmentioning

confidence: 99%

Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo

Edison¹,

Brosnan²,

Meyer³

et al. 2007

American Journal of Physiology-Renal Physiology

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Edison EE, Brosnan ME, Meyer C, Brosnan JT. Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo. Am J Physiol Renal Physiol 293: F1799-F1804, 2007. First published October 10, 2007; doi:10.1152/ajprenal.00356.2007.-A fraction of the body's creatine and creatine phosphate spontaneously degrades to creatinine, which is excreted by the kidneys. In humans, this amounts to ϳ1-2 g/day and demands a comparable rate of de novo creatine synthesis. This is a two-step process in which L-arginine:glycine amidinotransferase (AGAT) catalyzes the conversion of glycine and arginine to ornithine and guanidinoacetate (GAA); guanidinoacetate methyltransferase (GAMT) then catalyzes the S-adenosylmethioninedependent methylation of GAA to creatine. AGAT is found in the kidney and GAMT in the liver, which implies an interorgan movement of GAA from the kidney to the liver. We studied the renal production of this metabolite in both rats and humans. In control rats, [GAA] was 5.9 M in arterial plasma and 10.9 M in renal venous plasma for a renal arteriovenous (A-V) difference of Ϫ5.0 M. In the rat, infusion of arginine or citrulline markedly increased renal GAA production but infusion of glycine did not. Rats fed 0.4% creatine in their diet had decreased renal AGAT activity and mRNA, an arterial plasma [GAA] of 1.5 M, and a decreased renal A-V difference for GAA of Ϫ0.9 M. In humans, [GAA] was 2.4 M in arterial plasma, with a renal A-V difference of Ϫ1.1 M. These studies show, for the first time, that GAA is produced by both rat and human kidneys in vivo. L-arginine:glycine amidinotransferase; transamidinase; amino acid metabolism CREATINE AND CREATINE PHOSPHATE act to buffer the cytosolic ATP/ADP ratio in tissues that have high and variable rates of ATP usage (e.g., skeletal and cardiac muscle). Creatine kinase catalyzes the reversible transfer of the ␥-phosphate group of ATP to the guanidino group of creatine to yield ADP and creatine phosphate.ATP ϩ Creatine 7 ADP ϩ Creatine Phosphate (Equation 1) In skeletal muscle, creatine kinase activity is high, keeping its reaction at near-equilibrium. This keeps the ADP and ATP concentrations fairly constant and buffers the cytosolic phosphorylation potential (18,27,28). Energy storage and transmission by the creatine kinase system are hypothesized to work in two ways: as a temporal buffer and as a spatial buffer. The temporal energy buffer theory is best exemplified during episodes of high-energy use, such as muscle contraction. As soon as ATP is hydrolyzed, it must be replenished. The high-energy phosphate of creatine phosphate is transferred to ADP to regenerate ATP. This leads to an accumulation of creatine that must be rephosphorylated during recovery from exercise. The spatial energy buffer theory implies that creatine phosphate acts as an energy carrier, working to transport high-energy phosphate from sites of synthesis (mitochondria) to sites of ATP utilization in the cytosol (27

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Section: Discussionmentioning

confidence: 99%

Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo

Edison¹,

Brosnan²,

Meyer³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…This substance plays an important role in muscle energy metabolism as a precursor of creatine (CR) and is synthesized from arginine (Arg) and glycine (Gly) by glycine amidinotransferase(GAT) mainly in the kidney and thereafter to C'R by GAA methyltransferase (GAA-MT) in the liver [7][8][9], It has been reported that in uremia, GAA production is reduced because of decreased GAT activity in the kidney, resulting in a lower concentration of serum GAA with a significant negative correlation with blood urea nitrogen (BUN) [10][11][12][13]. It has been suggested that GAA deficiency caused by the reduced production of GAA re sults in a CR deficiency in the uremic state [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Study on Impaired Metabolism of Guanidinoacetic Acid in Chronic Renal Failure Rabbits with Special Reference to Impaired Conversion of Arginine to Guanidinoacetic Acid

Kuroda

1993

Nephron

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Most chronic renal failure (CRF) patients show low serum concentrations of guanidinoacetic acid (GAA). In this study, the author investigated the impaired metabolism of GAA in CRF focusing on the transformation of arginine (Arg) to GAA by analyzing CRF rabbits using ¹⁴C-Arg. The CRF group which consisted of 6 CRF rabbits, was compared with 6 normal rabbits (normal group). Blood samples were obtained from each abdominal aorta after a bolus injection of 30 μCi of ¹⁴C-Arg into an ear vein of each rabbit. After the last sampling, the left kidney was obtained for measurement of renal glycine amidinotransferase (GAT) activity. In each blood sample, the concentrations of blood urea nitrogen (BUN), serum creatinine (Cr), GAA and Arg were measured. The radioactivity of serum ¹⁴C-GAA was measured with a liquid scintillation system. Δ¹⁴C-GAA was calculated as the difference between the ¹⁴C-GAA count and the Δ¹⁴C -background count. Serum concentrations of GAA and renal GAT activity were significantly lower in the CRF group as compared with the normal group. Significant negative correlations were found between the two groups for the following comparisons: serum concentrations of Cr and GAA, concentrations of BUN and renal GAT activity, and serum concentrations of Cr and renal GAT activity. There was a significant positive correlation in the two groups, between renal GAT activity and serum concentrations of GAA. The fact that the concentrations of neither GAA nor Arg changed significantly after the injection of ¹⁴C-Arg in either group suggested that the dosage of injected Arg is not sufficient to affect the transformation of Arg to GAA. After 5 min and at the following 5-min intervals, Δ¹⁴C-GAA was significantly lower in the CRF group than in the normal group. There was a positive correlation between Δ¹⁴C-GAA after 5 min and renal GAT activity. These results clearly show that renal GAT activity decreases with the progression of renal dysfunction, which directly causes a reduced transformation of Arg to GAA in the kidney, resulting in lower serum concentrations of GAA.

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“…Regulation of creatine biosynthesis occurs at the level of AGAT, and increased creatine levels lower AGAT enzyme activity. 6 High AGAT activity is found in the kidney, but AGAT activity has also been reported in other tissues, including the pancreas, brain, spleen, and testes. 5 In the kidney, guanidinoacetate is synthesized exclusively in the proximal tubule.…”

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confidence: 99%

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

Dhayat

Simonin

Anderegg

et al. 2015

JASN

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A heterozygous mutation (c.643C.A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo. However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G.A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.

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Biosynthesis of Guanidinoacetic Acid in Isolated Renal Tubules

Cited by 22 publications

References 30 publications

Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo

Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo

Study on Impaired Metabolism of Guanidinoacetic Acid in Chronic Renal Failure Rabbits with Special Reference to Impaired Conversion of Arginine to Guanidinoacetic Acid

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

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