# Role of Inositol Hexakisphosphate Kinases in Vascular Smooth Muscle Cell Calcification

## TL;DR

This study explores how inositol hexakisphosphate kinases (IP6Ks) influence vascular smooth muscle cell calcification in chronic kidney disease.

## Contribution

The study identifies IP6K1 and IP6K2 as key regulators of phosphate-induced calcification in vascular smooth muscle cells.

## Key findings

- Silencing IP6K1 or IP6K2 reduces pro-calcific markers and calcification in vascular smooth muscle cells.
- IP6K2 silencing increases AKT phosphorylation, which is counteracted by AKT inhibition.
- SGK1 inhibition restores the protective effects of IP6K2 knockdown.

## Abstract

Phosphate-induced vascular calcification in chronic kidney disease is linked to cardiovascular mortality. This calcification process involves vascular smooth muscle cells (VSMCs), which can promote a pro-calcific environment in the vascular wall. However, the mechanisms underlying a putative phosphate sensing of VSMCs to modulate pro-calcific signaling are insufficiently clarified. In mammals, three isoforms of the inositol hexakisphosphate kinase (IP6K) exist, which have been implicated in cellular phosphate homeostasis. Therefore, each IP6K isoform was silenced in calcifying primary human aortic VSMCs. IP6K1 and IP6K2 mRNA expression were increased in calcifying VSMCs. Silencing of either IP6K1 or IP6K2 ameliorated phosphate-induced pro-calcific markers expression and VSMC calcification. IP6K3 mRNA expression was not modified during calcifying conditions, but IP6K3 silencing still resulted in some anti-calcific effects. Mechanistically, the IP6K product 5-IP7 may act as a potent inhibitor of AKT kinase signaling. Accordingly, pro-calcific conditions induced only transient AKT phosphorylation, and IP6K2 silencing increased AKT phosphorylation in calcifying VSMCs. In turn, AKT inhibition blunted the protective effects of IP6K2 knockdown, while serum- and glucocorticoid-inducible kinase 1 (SGK1) inhibition restored these effects. These observations indicate a role for IP6Ks during phosphate-induced VSMC calcification, which could be mediated by an altered balance between AKT and SGK1 signaling.