University of Osaka reveals syntaxin 3's role in kidney cell polarity, causing Fanconi syndrome

A research group including Hiroki Okushima (Graduate Student at the time of research), Assistant Professor Kazunori Inoue, Lecturer Isao Matsui, and Professor Yoshitaka Isaka from the Department of Nephrology, Graduate School of Medicine at the University of Osaka announced on December 12 that they had discovered the involvement of novel molecule "Syntaxin 3" in the expression of luminal-side receptors and transporters necessary for the reabsorption of substances from primary urine in kidney proximal tubular epithelial cells. They found that deficiency of this molecule impairs reabsorption, causing various substances to leak into the urine. This then leads to Fanconi syndrome. These results pave the way towards treatment development for Fanconi syndrome and elucidation of cell polarity control mechanisms. The results were published in Kidney International on September 29.

The kidney's proximal tubule is a tubular organ through which primary urine filtered by the glomerulus passes. By localizing transporters and receptors on the luminal side that comes into contact with primary urine, the body maintains homeostasis by reabsorbing various substances such as phosphorus, glucose, and amino acids from the primary urine. When reabsorption is impaired, these substances leak into the urine and become deficient, causing Fanconi syndrome with symptoms such as hypophosphatemia, rickets, and metabolic acidosis. Transporters and receptors are synthesized within cells, then transported to the luminal cell membrane. This occurs through vesicles which function by fusing with the cell membrane. It was known that interaction with SNARE proteins present on the luminal side is necessary during this fusion.

Previously, studies have shown that Syntaxin 3, one of the SNARE proteins, is expressed on the cell membrane in rat proximal tubules. In humans, Syntaxin 3 is reportedly expressed on the cell membrane of the small intestine, and mutations in this gene cause atrophy and mislocalization of small intestinal microvilli. This may lead to MVID (microvillus inclusion disease), characterized by intractable diarrhea from early infancy.

However, it remained unclear whether kidney proximal tubules are affected by MVID and what the disease state is if affected.

To address this gap, the research group first examined the localization of Syntaxin 3 in the proximal tubular epithelial cells of both humans and mice. They discovered it was localized on the luminal side in both.

Next, to clarify the function of Syntaxin 3 in proximal tubular epithelial cells, blood and urine were analyzed in two pediatric patients with MVID. The presence of microglobulin and cystine excreted in the urine revealed that both patients had developed Fanconi syndrome.

Based on these results, the researchers created Syntaxin 3-deficient mice, comparing their blood, urine, and tissues with those of wild-type mice.

The analysis revealed that substances that should normally be reabsorbed, such as phosphorus, glucose, cystine, and low-molecular-weight proteins, were increased in the urine of Syntaxin 3-deficient mice, causing Fanconi syndrome. In addition, deficient mice showed abnormalities such as dysplasia and mislocalization of microvilli, which are responsible for reabsorption, as well as the accumulation of vesicles just beneath the cell membrane.

Closer examination of the deficient mice revealed mislocalization of NaPi-IIa, a phosphorus transporter, and reduced expression of SGLT2, a glucose transporter.

These results demonstrate that Syntaxin 3 is critical for the cell polarity necessary for proximal tubular epithelial cells to perform their reabsorption function.

Okushima commented: "By revealing part of the mechanism for maintaining proximal tubule homeostasis, I hope that research on proximal tubules will advance further and treatment for Fanconi syndrome will improve. There are also molecules other than Syntaxin 3 involved in intracellular substance transport. In the future, I would like to comprehensively consider intracellular transport and elucidate these mechanisms."

Journal Information
Publication: Kidney International
Title: Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development
DOI: 10.1016/j.kint.2025.08.027