Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Acta Physiol (Oxf). 2019 Jan;225(1):e13175. doi: 10.1111/apha.13175. Epub 2018 Sep 3.
Alterations in parathyroid hormone (PTH) and/or vitamin D signalling are frequently reported in patients with sepsis. The consequences on renal and intestinal Ca and P regulatory mechanisms are still unclear. We hypothesized that endotoxaemia alters the expression of important renal and intestinal Ca and P transport proteins.
Male C57BL/6 mice were treated with lipopolysaccharide (LPS; 3 mg/kg; i.p.). The mRNA and protein levels of renal and intestinal Ca and P transport proteins were measured by RT-qPCR, immunohistochemistry and western blot analysis.
Lipopolysaccharide-induced hypocalcaemia and hyperphosphataemia was paralleled by a decrease in glomerular filtration rate and urinary excretion of Ca and P . Endotoxaemia augmented plasma levels of PTH and affected the fibroblast growth factor 23 (FGF23)-klotho-vitamin D axis by increasing plasma levels of FGF23 and downregulation of renal klotho expression. Renal expression of CYP27b1 and plasma levels of 1,25-dihydroxyvitamin D were increased in response to LPS. Endotoxaemia augmented the renal expression of TRPV5, TRPV6 and PiT1, whereas the renal expression of calbindin-D , NCX1, NaP -2a and NaP -2c were decreased. Incubation of primary distal tubule cells with LPS increased TRPV6 mRNA levels. Furthermore, LPS decreased the intestinal expression of TRPV6, calbindin-D and of NaP -2b.
Our findings indicate that endotoxaemia is associated with hypocalcaemia and hyperphosphataemia and a disturbed FGF23-klotho-vitamin D signaling. Further, LPS-induced acute kidney injury was accompanied by an increased or decreased expression of specific renal and intestinal Ca and P transporters respectively. It seems unlikely that LPS-induced hypocalcaemia is due to renal loss of Ca .
甲状旁腺激素（PTH）和/或维生素 D 信号的改变在脓毒症患者中经常被报道。但其对肾脏和肠道 Ca 和 P 调节机制的影响仍不清楚。我们假设内毒素血症会改变重要的肾脏和肠道 Ca 和 P 转运蛋白的表达。
雄性 C57BL/6 小鼠用脂多糖（LPS；3mg/kg；腹腔注射）处理。通过 RT-qPCR、免疫组织化学和 Western blot 分析测量肾脏和肠道 Ca 和 P 转运蛋白的 mRNA 和蛋白水平。
LPS 诱导的低钙血症和高磷血症与肾小球滤过率降低和尿钙和磷排泄减少有关。内毒素血症增加了 PTH 的血浆水平，并通过增加 FGF23 的血浆水平和下调肾脏 klotho 表达影响了成纤维细胞生长因子 23（FGF23）-klotho-维生素 D 轴。CYP27b1 的肾脏表达和 1,25-二羟基维生素 D 的血浆水平增加是对 LPS 的反应。内毒素血症增加了 TRPV5、TRPV6 和 PiT1 的肾脏表达，而 calbindin-D、NCX1、NaP-2a 和 NaP-2c 的肾脏表达减少。用 LPS 孵育原代远端肾小管细胞增加了 TRPV6 mRNA 水平。此外，LPS 降低了肠道 TRPV6、calbindin-D 和 NaP-2b 的表达。
我们的研究结果表明，内毒素血症与低钙血症和高磷血症以及 FGF23-klotho-维生素 D 信号紊乱有关。此外，LPS 诱导的急性肾损伤伴有特定肾脏和肠道 Ca 和 P 转运蛋白的表达增加或减少。LPS 诱导的低钙血症似乎不是由于肾脏钙丢失引起的。
