Division of Nephrology, Department of Medicine, and.
Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
J Clin Invest. 2023 May 1;133(9):e169607. doi: 10.1172/JCI169607.
The proximal tubule is the high-capacity reabsorptive powerhouse of the kidney. Two papers in recent issues of the JCI highlight mechanisms of more delicate effects of the proximal tubule. Yoon et al. demonstrated the intracellular mechanism by which parathyroid hormone (PTH) increases production of 1,25-vitamin D. Activation of PTH receptor 1/cAMP/PKA signaling inhibited salt-inducible kinase 2 (SIK2) and SIK3, which increased CYB27B1 transcription and 1,25-vitamin D production. Replication of these effects with small-molecule SIK inhibitors suggests possible therapeutic applications for patients with disorders characterized by 1,25-vitamin D deficiency. Zhou et al. discovered that proximal tubule glycolysis acts as a phosphate sensor that regulates fibroblast growth factor 23 production in bone. They described several kidney-specific metabolic modifications that enabled glycolysis to be deployed as a phosphate sensor. The provocative results raise intriguing questions with implications for patients with disorders of phosphate homeostasis, including chronic kidney disease.
近端小管是肾脏的高容量重吸收功能单位。近期《临床检查杂志》（JCI）的两篇论文强调了近端小管更精细作用的机制。Yoon 等人证明了甲状旁腺激素（PTH）增加 1,25-维生素 D 产生的细胞内机制。PTH 受体 1/cAMP/PKA 信号的激活抑制盐诱导激酶 2（SIK2）和 SIK3，从而增加 CYB27B1 转录和 1,25-维生素 D 的产生。用小分子 SIK 抑制剂复制这些作用表明，对于以 1,25-维生素 D 缺乏为特征的疾病患者，可能具有治疗应用。Zhou 等人发现，近端小管糖酵解作为磷酸盐传感器，调节骨中成纤维细胞生长因子 23 的产生。他们描述了几种肾脏特异性代谢修饰，使糖酵解能够作为磷酸盐传感器发挥作用。这些有启发性的结果提出了一些有趣的问题，这些问题可能与磷酸盐稳态紊乱的患者有关，包括慢性肾脏病。
