title: Uric acid, indoxyl sulfate, and methylguanidine activate bulbospinal neurons in the RVLM via their specific transporters and by producing oxidative stress.
abstract: Patients with chronic renal failure often have hypertension, but the cause of hypertension, other than an excess of body fluid, is not well known. We hypothesized that the bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are stimulated by uremic toxins in patients with chronic renal failure. To investigate whether RVLM neurons are sensitive to uremic toxins, such as uric acid, indoxyl sulfate, or methylguanidine, we examined changes in the membrane potentials (MPs) of bulbospinal RVLM neurons of Wister rats using the whole-cell patch-clamp technique during superfusion with these toxins. A brainstem-spinal cord preparation that preserved the sympathetic nervous system was used for the experiments. During uric acid, indoxyl sulfate, or methylguanidine superfusion, almost all the RVLM neurons were depolarized. To examine the transporters for these toxins on RVLM neurons, histological examinations were performed. The uric acid-, indoxyl sulfate-, and methylguanidine-depolarized RVLM neurons showed the presence of urate transporter 1 (URAT 1), organic anion transporter (OAT)1 or OAT3, and organic cation transporter (OCT)3, respectively. Furthermore, the toxin-induced activities of the RVLM neurons were suppressed by the addition of an anti-oxidation drug (VAS2870, an NAD(P)H oxidase inhibitor), and a histological examination revealed the presence of NAD(P)H oxidase (nox)2 and nox4 in these RVLM neurons. The present results show that uric acid, indoxyl sulfate, and methylguanidine directly stimulate bulbospinal RVLM neurons via specific transporters on these neurons and by producing oxidative stress. These uremic toxins may cause hypertension by activating RVLM neurons.
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan. Electronic address: oshima@ndmc.ac.jp.
authors.forename: N
authors.initials: N
authors.lastname: Oshima
authors.affiliation: Department of Physiology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Onimaru
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takechi
authors.affiliation: Department of Physiology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kumagai
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism; D001583:Benzoxazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007200:Indican / Q000633:toxicity*; D008526:Medulla Oblongata / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008760:Methylguanidine / Q000633:toxicity*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014230:Triazoles / Q000494:pharmacology; D014527:Uric Acid / Q000633:toxicity*
chemical_list: C511179:3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine; D027321:Anion Transport Proteins; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C554079:Slc22a12 protein, rat; C421043:Slc22a6 protein, rat; D014230:Triazoles; C114338:organic anion transport protein 3; D014527:Uric Acid; D008760:Methylguanidine; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D007200:Indican
keywords: OAT3; RVLM neurons; URAT1; nox4; uremic toxins