Kidney Week

Abstract: SA-PO0875

Sustained Creatine Deficiency Reprograms Kidney Metabolism via Peroxisome Proliferator-Activated Receptor α and FOXO1

Session Information

• Health Maintenance, Nutrition, and Metabolism
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Health Maintenance, Nutrition, and Metabolism

• 1500 Health Maintenance, Nutrition, and Metabolism

Authors

• Singal, Rhea, Washington University in St Louis, St. Louis, Missouri, United States

Rhea Singal

• Gewin, Leslie S., Washington University in St Louis, St. Louis, Missouri, United States

Leslie S. Gewin, MD, FASN

• Civitelli, Roberto, Washington University in St Louis, St. Louis, Missouri, United States

Roberto Civitelli, MD

• Portales Castillo, Ignacio A., Washington University in St Louis, St. Louis, Missouri, United States

Ignacio A. Portales Castillo, MD

Background

The Glycine Amidinotransferase (GATM), located in proximal tubules, is required to synthesize creatine. The creatine/phosphocreatine system serves to provide a high energy phosphate to convert adenosine monophosphate (AMP) to adenosine triphosphate (ATP). Using a mouse model null for GATM, it was previously shown that low systemic creatine results in higher tissue AMP levels and is protective from metabolic syndrome caused by high fat diet, in part by increasing hepatic β oxidation. However, the metabolic response of kidneys under conditions of systemic creatine deficiency has not been described.

Methods

We generated a new mouse model with the GATM P341L mutant found in humans with Fanconi syndrome and mild defect in creatine synthesis due to heterozygous mutations.

Results

We found that unlike humans, mice with the GATM P341L mutation do not develop renal injury, likely because the mutant protein is profoundly downregulated in this model and homozygous mutant mice (GATM^P341L/P341L) become creatine deficient but renal ATP levels remain normal.
In healthy kidneys, fatty acid oxidation (FAO) is the main source of ATP. We therefore sought evidence of changes in FAO associated metabolites and genes in GATM^P341L/P341L mice. We found that the peroxisome proliferator-activated receptor alpha (PPARα), the key regulator of kidney FAO was increased in adult GATM^P341L/P341L mice. In line, Acyl-CoA Oxidase 1 (ACOX1), the first enzyme of the fatty acid beta-oxidation pathway ,the nicotinamide mononucleotide (NMN), which is precursor of NAD+/NADH and Palmitoyl carnitine, an intermediate to transport fatty acids into the mitochondria were all higher in GATM^P341L/P341L mice. Interestingly, at 12 months we observed the presence of lipid vacuoles in wild-type mice but not in GATM^P341L/P341L mice, suggesting possible age protective effects of chronic creatine deficiency in the kidney. RNA-seq data followed by KEGG pathway analysis revealed Forkhead box protein O1, typically active during starvation response, as the highest upregulated pathway, which we validated by increased nuclear staining of FOXO1 in GATM^P341L/P341L mice as well as increased autophagy flux.

Conclusion

Our data shows that downregulation of GATM leads to systemic creatine deficiency. Upon creatine deficiency, PPARα and FOXO1 are activated, likely as compensatory energy responses, which may also protect from chronic kidney disease.

Funding

• NIDDK Support