PhD Scientific Days 2026

Theoretical and Translational Medicine 4.

The Central Role of ABCC6 in Phosphate Induced Pyrophosphate Response

Name of the presenter

Várhegyi, Martin

Institute/workplace of the presenter

Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary

Authors

Martin Várhegyi¹, Virgil Christian Tamatey¹, Dr. Flóra Szeri¹
1: Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary

Text of the abstract

Introduction
Extracellular inorganic pyrophosphate (PPi) is a well-known inhibitor of soft tissue calcification, it prevents calcium phosphate crystal growth. The main sources of PPi in body fluids are two membrane proteins, ANK and ABCC6. ANK is expressed in various tissues, whereas ABCC6 is expressed mainly in the liver and, to a lesser extent, in the kidney, where its function remains unclear. ABCC6 deficiency results in reduced plasma PPi levels in both humans and mice, leading to progressive soft tissue calcification. Studies from the 1960s and 1970s reported that phosphate administration increases urinary PPi excretion in humans and dogs; however, this observation was not incorporated into current knowledge, probably due to misinterpretation of the underlying process.
Aims
We aimed to confirm the existence of the phosphate induced PPi response and to determine its dependence on ABCC6 using Abcc6 -/- and WT mice.
Methods
Abcc6 -/- and WT mice received phosphate solution by feeding tube or intraperitoneal injection, and plasma and urinary PPi concentrations were determined using a bioluminescent assay.
Results
In WT mice, both phosphate treatments increased urinary PPi concentration by 3- to 4-fold. Orally administered phosphate increased plasma PPi concentration by 60%, whereas intraperitoneal phosphate did not. In Abcc6 -/- mice, phosphate treatment had only a slight effect on urinary PPi, and no increase in plasma PPi was observed.
Conclusion
The phosphate induced PPi response does exist, and ABCC6 plays a central role in this physiological phenomenon. Increased phosphate concentration in body fluids can promote calcium phosphate precipitation and deposition in soft tissues, and our findings suggest that a biological response exists that increases PPi production as an anti-mineralization factor to counteract this process. These results further suggest that ABCC6 may function as a mineralization stress protein and may point to a previously unknown role of ABCC6 in the kidney. Further investigation of the underlying mechanism of this response may identify a potential therapeutic target for the prevention or treatment of soft tissue calcification.
Funding: Predoctoral Scholarship