Extracellular Pyrophosphate in the Kidney: How Does It Get There and What Does It Do

Pyrophosphate (PPi) is well known as a regulator of calcification, and the ANKH (ANK in mouse) protein has a role in the membrane transport of PPi. Earlier work concentrated on bones and joints, but ANKH is also likely to have important roles in the kidney, with newer studies focusing on vascular calcification in renal failure. Renal calcification can occur due to a naturally occurring ANK mouse mutation, yet other ANK mutations do not cause a renal phenotype. Despite evidence over 10 years of ANKH's involvement in PPi transport, efflux of PPi via ANKH has never been demonstrated. Rather than physically moving PPi, the ANKH protein may assist its membrane transport in other ways such as by hydrolysis and compartmentalisation. Protein complexes may account for effects of ANKH that are specific to particular tissues. In the kidney, recent localisation data may be helpful in suggesting physiological roles for ANKH, such as its co-localisation with aquaporin-2 and cilial proteins. Such diverse functions would reflect the ubiquitous nature of ANKH in tissues and its profound evolutionary conservation.