The Ip6k1 and Ip6k2 kinases are critical for normal renal tubular function

Haykir B; Moser SO; Pastor-Arroyo EM; Schnitzbauer U; Radvanyi Z; Prucker I; Qiu D; Fiedler D; Saiardi A; Jessen HJ; Hernando N; Wagner CA

doi:10.1530/ey.22.5.13

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 5.13 | DOI: 10.1530/ey.22.5.13

ESPEYB25 5. Bone, Growth Plate and Mineral Metabolism Advances in Growth, Bone Biology and Mineral Metabolism (2 abstracts)

5.13. The Ip6k1 and Ip6k2 kinases are critical for normal renal tubular function

Haykir B , Moser SO , Pastor-Arroyo EM , Schnitzbauer U , Radvanyi Z , Prucker I , Qiu D , Fiedler D , Saiardi A , Jessen HJ , Hernando N & Wagner CA

Journal of the American Society of Nephrology. (2024). 35(4), 441-455. https://doi.org/10.1681/ASN.0000000000000303

Brief Summary: This study used both in vitro opossum kidney cells and in vivo renal tubular-specific IP6K1/2 knockout mice to investigate the role of IP6K1/2 kinases in phosphate homeostasis. Depleting these kinases impaired phosphate transport and disrupted other kidney functions, particularly in males.

Commentary: Inorganic phosphate is an essential mineral whose tightly controlled plasma levels are crucial for various biological processes, including the formation of cellular membranes, DNA and RNA, and bones. Dysregulation can lead to severe health issues such as hyperphosphatemia, which is associated with cardiovascular disease, or hypophosphatemia, which affects bone. The kidneys play a central role in maintaining this balance by regulating phosphate reabsorption, primarily through Na/Pi cotransporters such as NaPi-IIa and NaPi-IIc in the proximal tubules. Although 5-IP7, an inositol pyrophosphate generated by IP6Ks, is known to regulate phosphate metabolism in yeast and plants, its role in mammalian phosphate homeostasis remains largely unexplored.

This study demonstrates that IP6K1 and IP6K2 are essential for the normal functioning of the renal tubule in mammals. Depletion of these kinases in both in vitro and in vivo models was found to lead to reduced phosphate transport and altered expression of key Na+/Pi cotransporters. Specifically, male IP6K1/2 knockout mice developed hypophosphataemia, increased bone resorption and general tubular dysfunction, including increased diuresis, albuminuria and hypercalciuria. These findings highlight the essential role of IP6Ks in not only phosphate metabolism, but also broader kidney functions, suggesting a more complex role than previously thought. However, these findings also suggest that, while pharmacological inhibition of these kinases could potentially target phosphate metabolism, it could lead to severe and undesirable side effects due to their broader impact on kidney function.

Further research is needed to clarify the therapeutic potential and safety considerations of targeting IP6K pathways for phosphate-related disorders.