Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Department of Physiology, Showa University School of Medicine, Tokyo, Japan.
Auton Neurosci. 2020 Mar;224:102640. doi: 10.1016/j.autneu.2020.102640. Epub 2020 Jan 25.
Hypertension often occurs in patients with chronic kidney disease (CKD). Considering the decrease in serum Klotho and increase in serum FGF23 levels in such patients, decreased Klotho and increased FGF23 levels were thought to be associated with hypertension. Presympathetic neurons at the rostral ventrolateral medulla (RVLM) contribute to sympathetic activity and regulation of blood pressure. Therefore, we hypothesized that Klotho would reduce the activities of RVLM neurons and FGF23 would stimulate them. Accordingly, this study examined the effects of Klotho and FGF23 on bulbospinal neurons in the RVLM. We used a brainstem-spinal cord preparation to record from RVLM presympathetic neurons and to evaluate the effects of Klotho and FGF23 on firing rate and membrane potentials of these neurons. Our results showed that Klotho-induced RVLM neuron hyperpolarization, while ouabain, a Na/K-ATPase inhibitor, suppressed the effects of Klotho on such neurons. Moreover, FGF23 induced RVLM neuron depolarization, while SU5402, an FGF23 receptor (FGFR1) antagonist, induced RVLM neuron hyperpolarization. Histological examinations revealed that Klotho, Na/K-ATPase, FGF23, and FGFR1 were present in RVLM neurons and that Klotho was localized in the same neurons as FGFR1. These results suggest that Klotho and FG23 regulate the activity of RVLM neurons. Klotho may reduce the activity of RVLM neurons via stimulating Na/K-ATPase on those neurons while FGF23 may activate those neurons via FGFR1.
高血压常发生于慢性肾脏病（CKD）患者中。鉴于此类患者血清 Klotho 水平降低和血清 FGF23 水平升高，推测 Klotho 降低和 FGF23 升高与高血压相关。延髓头端腹外侧区（RVLM）的前交感神经元参与交感神经活动和血压调节。因此，我们假设 Klotho 会降低 RVLM 神经元的活性，而 FGF23 会刺激它们。相应地，本研究检测了 Klotho 和 FGF23 对 RVLM 中的延髓脊髓神经元的影响。我们使用脑干脊髓制备来记录 RVLM 前交感神经元，并评估 Klotho 和 FGF23 对这些神经元的放电率和膜电位的影响。我们的结果表明，Klotho 诱导 RVLM 神经元超极化，而 Na/K-ATP 酶抑制剂哇巴因则抑制 Klotho 对这些神经元的作用。此外，FGF23 诱导 RVLM 神经元去极化，而 FGFR1 拮抗剂 SU5402 则诱导 RVLM 神经元超极化。组织学检查显示，Klotho、Na/K-ATP 酶、FGF23 和 FGFR1 存在于 RVLM 神经元中，并且 Klotho 定位于与 FGFR1 相同的神经元中。这些结果表明，Klotho 和 FGF23 调节 RVLM 神经元的活性。Klotho 可能通过刺激神经元上的 Na/K-ATP 酶来降低 RVLM 神经元的活性，而 FGF23 可能通过 FGFR1 来激活这些神经元。
