The solute carrier SLC16A12 is critical for creatine and guanidinoacetate handling in the kidney

Verouti, Sophia N; Lambert, Delphine; Mathis, Déborah; Pathare, Ganesh; Escher, Geneviève; Vogt, Bruno; Fuster, Daniel G. (2021). The solute carrier SLC16A12 is critical for creatine and guanidinoacetate handling in the kidney. American journal of physiology. Renal physiology, 320(3), F351-F358. American Physiological Society 10.1152/ajprenal.00475.2020

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A heterozygous mutation (c.643C.A; p.Q215X) in the creatine transporter SLC16A12 was proposed to cause a syndrome with juvenile cataracts, microcornea and glucosuria in humans. To further explore the role of SLC16A12 in renal physiology and decipher the mechanism underlying the phenotype of humans with the SLC16A12 mutation, we studied Slc16a12 knock-out (KO) rats. Slc16a12 KO rats had lower plasma levels and increased absolute and fractional urinary excretion of creatine and its precursor guanidinoacetate (GAA). Slc16a12 KO rats displayed lower plasma and urinary creatinine levels, but GFR was normal. The phenotype of heterozygous rats was indistinguishable from wild-type (WT) rats. Renal artery to vein (RAV) concentration differences in WT rats were negative for GAA and positive for creatinine. However, RAV differences for GAA were similar in Slc16a12 KO rats, indicating incomplete compensation of urinary GAA losses by renal GAA synthesis. Together, our results reveal that Slc16a12 in the basolateral membrane of the proximal tubule is critical for reabsorption of creatine and GAA. Our data suggest a dominant-negative mechanism underlying the phenotype of humans affected by the heterozygous SLC16A12 mutation. Furthermore, in the absence of Slc16a12, urinary losses of GAA are not adequately compensated by increased tubular synthesis, caused by feedback inhibition of the rate limiting enzyme L-arginine:glycine amidinotransferase by creatine in proximal tubular cells.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie

UniBE Contributor:

Lambert, Delphine Jeanne Colette; Escher, Geneviève; Vogt, Bruno and Fuster, Daniel Guido

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1522-1466

Publisher:

American Physiological Society

Language:

English

Submitter:

Daniel Fuster

Date Deposited:

11 Feb 2021 10:41

Last Modified:

11 Mar 2021 01:34

Publisher DOI:

10.1152/ajprenal.00475.2020

PubMed ID:

33459166

BORIS DOI:

10.48350/151466

URI:

https://boris.unibe.ch/id/eprint/151466

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