tasis is mostly unknown. We demonstrate in a renal cell line and in mice that Ip6k1 and Ip6k2 are critical for normal expression and function of the major renal Na+/Pi transporters NaPi-IIa and NaPi-IIc. Moreover, Ip6k1/2−/− mice also show symptoms of more generalized kidney dysfunction. Thus, our results suggest that IP6Ks are essential for phosphate metabolism and proper kidney function in mammals. Background Inorganic phosphate is an essential mineral, and its plasma levels are tightly regulated. In mammals, kidneys are critical for maintaining phosphate homeostasis through mechanisms that ultimately regulate the expression of the Na+/Pi cotransporters NaPi-IIa and NaPi-IIc in proximal tubules. Inositol pyrophosphate 5-IP7, generated by IP6Ks, is a main regulator of phosphate metabolism in yeast and plants. IP6Ks are conserved in mammals, but their role in phosphate metabolism in vivo remains unexplored. Methods We used in vitro (opossum kidney cells) and in vivo (renal tubular-specific Ip6k1/2−/−mice) models to analyze the role of IP6K1/2 in phosphate homeostasis in mammals. Results In both systems, Ip6k1 and Ip6k2 are responsible for synthesis of 5-IP7. Depletion of Ip6k1/2 in vitro reduced phosphate transport and mRNA expression of Na+/Pi cotransporters, and it blunts phosphate transport adaptation to changes in ambient phosphate. Renal ablation of both kinases in mice also downregulates the expression of NaPi-IIa and NaPi-IIc and lowered the uptake of phosphate into proximal renal brush border membranes. In addition, the absence of Ip6k1 and Ip6k2 reduced the plasma concentration of fibroblast growth factor 23 and increased bone resorption, despite of which homozygous males develop hypophosphatemia. Ip6k1/2−/− mice also show increased diuresis, albuminuria, and hypercalciuria, although the morphology of glomeruli and proximal brush border membrane seemed unaffected. Conclusions Depletion of renal Ip6k1/2 in mice not only altered phosphate homeostasis but also dysregulated other kidney functions....

中文翻译：

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Ip6k1 和 Ip6k2 激酶对于正常肾小管功能至关重要

塔西斯大多是未知的。我们在肾细胞系和小鼠中证明，Ip6k1 和 Ip6k2 对于主要肾脏 Na+/Pi 转运蛋白 NaPi-IIa 和 NaPi-IIc 的正常表达和功能至关重要。此外，Ip6k1/2−/− 小鼠还表现出更广泛的肾功能障碍的症状。因此，我们的结果表明 IP6K 对于哺乳动物的磷酸盐代谢和正常的肾功能至关重要。背景 无机磷酸盐是一种必需矿物质，其血浆水平受到严格调节。在哺乳动物中，肾脏通过最终调节近端小管中 Na+/Pi 协同转运蛋白 NaPi-IIa 和 NaPi-IIc 表达的机制，对于维持磷酸盐稳态至关重要。肌醇焦磷酸 5-IP7 由 IP6K 产生，是酵母和植物中磷酸盐代谢的主要调节剂。 IP6K 在哺乳动物中是保守的，但它们在体内磷酸盐代谢中的作用仍未被探索。方法 我们使用体外（负鼠肾细胞）和体内（肾小管特异性 Ip6k1/2−/− 小鼠）模型来分析 IP6K1/2 在哺乳动物磷酸盐稳态中的作用。结果 在两个系统中，Ip6k1 和 Ip6k2 负责合成 5-IP7。体外 Ip6k1/2 的耗竭会减少磷酸盐转运和 Na+/Pi 协同转运蛋白的 mRNA 表达，并削弱磷酸盐转运对环境磷酸盐变化的适应。小鼠肾脏消融这两种激酶也会下调 NaPi-IIa 和 NaPi-IIc 的表达，并降低近端肾刷状缘膜对磷酸盐的摄取。此外，Ip6k1和Ip6k2的缺失降低了成纤维细胞生长因子23的血浆浓度并增加了骨吸收，尽管如此，纯合子男性仍会出现低磷血症。 Ip6k1/2−/− 小鼠也表现出利尿、蛋白尿和高钙尿增加，尽管肾小球和近端刷状缘膜的形态似乎不受影响。结论 小鼠肾脏 Ip6k1/2 的耗竭不仅改变了磷酸盐稳态，而且还导致其他肾功能失调......