PDF(Pubmed)
Abstract：
Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.
摘要：
慢性肾病的许多病理后果可归因于血清磷酸盐水平的升高。目前集中于减少肠磷酸盐吸收以治疗高磷酸盐血症的疗法是不充分的。最有效的治疗策略可能是靶向多个吸收途径。在这项研究中,肠钠氢交换剂3（NHE3）的新型抑制剂的能力，LY3304000，抑制细胞旁，磷酸盐的扩散吸收，与活性转运蛋白的抑制剂结合工作，钠依赖性磷酸盐协同转运蛋白2b（NPT2b），LY3358966，进行了探索。LY3304000适度抑制大鼠血浆中磷酸盐的急性摄取，虽然令人惊讶，它使小鼠的磷酸盐摄取率增加了一倍，以NPT2b介导的急性磷酸盐摄取为主的动物模型。在老鼠身上,LY3004000和LY3358966协同工作以抑制急性磷酸盐摄取。在LY3358966之上,LY3304000进一步下降了急性摄取磷酸盐进入血浆。测量肠中放射性标记磷酸盐的回收率的研究表明，LY3304000和LY3358966协同抑制了大鼠磷酸盐的吸收。我们假设协同作用是因为NHE3抑制剂，LY3304000对大鼠肠道磷酸盐吸收有两种相反的作用，首先它减少扩散介导的细胞旁磷酸盐吸收，而第二,它同时通过NPT2b途径增加磷酸盐吸收。NHE3抑制减少从肠细胞的质子输出并提高细胞表面pH。体外，NPT2b介导的磷酸盐转运在较高的pH下增加。在NPT2b介导的磷酸盐转运水平相对较低的大鼠中，由NHE3抑制诱导的NPT2b介导的转运增加被掩盖。通过对扩散介导的磷酸盐吸收的更强大的抑制。因此，在存在NHE3抑制的情况下，大鼠中NPT2b介导的磷酸盐转运的抑制具有超过其在不存在NHE3抑制的情况下的作用，导致观察到的NPT2b和NHE3抑制之间对磷酸盐吸收的协同作用。
