Abstract
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.
Highlights
Klotho (1014 amino acids; molecular weight, 130 kDa), which is mainly produced in the distal convoluted tubules of the kidneys, parathyroid glands, and choroid plexus of the brain, is known as an anti-aging and anti-inflammatory protein (Clinton et al, 2013; Kuro-o, 2008; Kurosu et al, 2005)
Given previous reports showing that Klotho increases Na+/ K+-ATPase activity (Sopjani et al, 2011; Tang et al, 2018), we examined whether Na+/K+-ATPase is related to the Klotho-induced changes in rostral ventrolateral medulla (RVLM) neuron membrane potentials (MPs)
Increased activity of the RVLM presympathetic neurons is transmitted to the intermediolateral cell column (IML) in the spinal cord, where peripheral sympathetic nerves activated, causing blood pressure (BP) elevation (Pilowsky and Goodchild, 2002) and decreased activity of these neurons leads to BP reduction (Zanzinger et al, 1995)
Summary
Klotho (1014 amino acids; molecular weight, 130 kDa), which is mainly produced in the distal convoluted tubules of the kidneys, parathyroid glands, and choroid plexus of the brain, is known as an anti-aging and anti-inflammatory protein (Clinton et al, 2013; Kuro-o, 2008; Kurosu et al, 2005). A previous study indicated that silencing brain Klotho through intracerebroventricular injections of adeno-associated virus with KlothoshRNA resulted in earlier BP elevation in rats (Wang and Sun, 2010), while Klotho gene delivery improves hypertension (Wang and Sun, 2009). These studies demonstrated that reduced Klotho in the brain increases brain endothelin expression and activates sympathetic nervous system activity (Wang and Sun, 2010). The present study examined the direct effects of Klotho and FGF23 on bulbospinal RVLM neurons using brainstem–spinal cord preparations (Oshima et al, 2015) and employed histological analyses to examine the presence of Klotho, Na+/K+-ATPase, FGF23, and FGF23R1 in RVLM neurons
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