Masashi Suzuki

Publications (12)54.57 Total impact

• Article: Identification of dominant negative effect of L522P mutation in the electrogenic Na(+)-HCO 3 (-) cotransporter NBCe1.

  Osamu Yamazaki, Hideomi Yamada, Masashi Suzuki, Shoko Horita, Ayumi Shirai, Motonobu Nakamura, Nobuhiko Satoh, Toshiro Fujita, George Seki
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  ABSTRACT: Homozygous mutations in the electrogenic Na(+)-HCO3 (-) cotransporter NBCe1 cause proximal renal tubular acidosis (pRTA) associated with extrarenal manifestations such as ocular abnormalities and migraine. Previously, the NBCe1 cytosolic mutant S982NfsX4 was shown to have a dominant negative effect by forming hetero-oligomer complexes with wild type (WT), which might be responsible for the occurrence of glaucoma and migraine in the heterozygous family members. In this study, we investigated whether the NBCe1 L522P mutant has a similar dominant negative effect. Functional analyses in Xenopus oocytes and HEK293 cells revealed that the L522P mutant had no transport activity due to defective membrane expression. Furthermore, when coexpressed with WT, L522P significantly reduced the transport activity of WT. In HEK293 cells, the cytosolic mutant L522P reduced the membrane expression of NBCe1 by forming hetero-oligomer complexes with WT. Among the artificial Leu(522) mutants, L522I showed proper membrane expression and normal transport activity. However, the other mutants L522R, L522K, L522D, and L522E showed a predominant cytosolic retention. Moreover, L522R had a dominant negative effect, when coexpressed with WT. These results indicate that Leu(522) plays an important role in the structure and trafficking of NBCe1. They also suggest that the NBCe1 mutants retaining in cytoplasm may have the dominant negative effect in common, which may induce some clinical manifestations.
  Pflügers Archiv - European Journal of Physiology 04/2013; · 4.46 Impact Factor
• Source

  Available from: PubMed Central

  Article: Functional Roles of Electrogenic Sodium Bicarbonate Cotransporter NBCe1 in Ocular Tissues.

  Masashi Suzuki, George Seki, Hideomi Yamada, Shoko Horita, Toshiro Fujita
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  ABSTRACT: Electrogenic Na(+)-HCO(3) (-) cotransporter NBCe1 is expressed in several tissues such as kidney, eye, and brain, where it may mediate distinct biological processes. In particular, NBCe1 in renal proximal tubules is essential for the regulation of systemic acid/base balance. On the other hand, NBCe1 in eye may be indispensable for the maintenance of tissue homeostasis. Consistent with this view, homozygous mutations in NBCe1 cause severe proximal renal tubular acidosis associated with ocular abnormalities such as band keratopathy, glaucoma, and cataract. The widespread expression of NBCe1 in eye suggests that the inactivation of NBCe1 per se may be responsible for the occurrence of these ocular abnormalities. In this review, we discuss about physiological and pathological roles of NBCe1 in eye.
  The Open Ophthalmology Journal 01/2012; 6:36-41.
• Article: Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling.

  Yoko Endo, Masashi Suzuki, Hideomi Yamada, Shoko Horita, Motoei Kunimi, Osamu Yamazaki, Ayumi Shirai, Motonobu Nakamura, Naoyuki Iso-O, Yuehong Li, [......], Akihiko Kudo, Hayato Kawakami, Toshimasa Yamauchi, Naoto Kubota, Takashi Kadowaki, Haruki Kume, Yutaka Enomoto, Yukio Homma, George Seki, Toshiro Fujita
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  ABSTRACT: Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARγ-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion.
  Cell metabolism 05/2011; 13(5):550-61. · 17.35 Impact Factor
• Article: Functional role of a putative carbonic anhydrase II-binding domain in the electrogenic Na+ -HCO₃- cotransporter NBCe1 expressed in Xenopus oocytes.

  Hideomi Yamada, Shoko Horita, Masashi Suzuki, Toshiro Fujita, George Seki
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  ABSTRACT: The electrogenic Na+ -HCO₃⁻ cotransporter NBCe1 plays essential roles in the regulation of systemic and/or local pH. Homozygous inactivating mutations in NBCe1 cause proximal renal tubular acidosis associated with ocular abnormalities. We recently showed that defective membrane expression of NBCe1, caused by several mutations such as Delta65bp (S982NfsX4), is also associated with familial migraine. The Delta65bp mutant is quite unique in that it lacks a putative carbonic anhydrase (CA) II-binding domain but still shows an apparently normal transport activity in Xenopus oocytes. In this addendum, we show that the co-expression of CAII together with the wild-type NBCe1 or the Delta65bp mutant does not enhance the NBCe1 activities in oocytes. Moreover, a carbonic anhydrase inhibitor acetazolamide fails to inhibit the wild-type or the Delta65bp activities co-expressed with CAII. These results indicate that a bicarbonate transport metabolon proposed for the interaction between CAII and NBCe1 does not work at least in Xenopus oocytes.
  Channels (Austin, Tex.) 03/2011; 5(2):106-9. · 1.91 Impact Factor
• Article: Functional characterization of nonsynonymous single nucleotide polymorphisms in the electrogenic Na+-HCO3- cotransporter NBCe1A.

  Osamu Yamazaki, Hideomi Yamada, Masashi Suzuki, Shoko Horita, Ayumi Shirai, Motonobu Nakamura, George Seki, Toshiro Fujita
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  ABSTRACT: The electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1 encoded by SLC4A4 plays essential roles in the regulation of intracellular/extracellular pH. Homozygous mutations in NBCe1 cause proximal renal tubular acidosis associated with ocular abnormalities. In the present study, we tried to perform functional characterization of the four nonsynonymous single nucleotide polymorphisms (SNPs), E122G, S356Y, K558R, and N640I in NBCe1A. Functional analysis in Xenopus oocytes revealed that while the K558R variant had a significantly reduced transport activity corresponding to 47% of the wild-type activity, the remaining variants E122G, S356Y, and N640I did not change the NBCe1A activity. Apparent Na(+) affinity of K558R was not different from that of wild-type NBCe1A. Immunohistological analyses in HEK293 cells and MDCK cells indicated that none of these SNPs changed the trafficking behaviors of NBCe1A. Functional analysis in HEK293 cells also revealed that only the K558R variant had a reduced transport activity, corresponding to 41-47% of the wild-type activity. From these results, we conclude that among four SNPs, only the K558R variant, which is predicted to lie in transmembrane segment 5, significantly reduces the NBCe1A activity without changing the trafficking behavior or the apparent extracellular Na(+) affinity.
  Pflügers Archiv - European Journal of Physiology 02/2011; 461(2):249-59. · 4.46 Impact Factor
• Article: [Renal tubular acidosis].

  George Seki, Shoko Horita, Masashi Suzuki, Hideomi Yamada
  Nippon Jinzo Gakkai shi 01/2011; 53(2):173-6.
• Source

  Available from: PubMed Central

  Article: Insulin resistance, obesity, hypertension, and renal sodium transport.

  Shoko Horita, George Seki, Hideomi Yamada, Masashi Suzuki, Kazuhiko Koike, Toshiro Fujita
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  ABSTRACT: Sodium transport through various nephron segments is quite important in regulating sodium reabsorption and blood pressure. Among several regulators of this process, insulin acts on almost all the nephron segments and is a strong enhancer of sodium reabsorption. Sodium-proton exchanger type 3 (NHE3) is a main regulator of sodium reabsorption in the luminal side of proximal tubule. In the basolateral side of the proximal tubule, sodium-bicarbonate cotransporter (NBCe1) mediates sodium and bicarbonate exit from tubular cells. In the distal nephron and the connecting tubule, epithelial sodium channel (ENaC) is of great importance to sodium reabsorption. NHE3, NBCe1, and ENaC are all regulated by insulin. Recently with-no-lysine (WNK) kinases, responsible for familial hypertension, stimulating sodium reabsorption in the distal nephron, have been found to be also regulated by insulin. We will discuss the regulation of renal sodium transport by insulin and its roles in the pathogenesis of hypertension in insulin resistance.
  International journal of hypertension. 01/2011; 2011:391762.
• Source

  Available from: Bruno Bergmans

  Article: Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine.

  Masashi Suzuki, Wim Van Paesschen, Ingeborg Stalmans, Shoko Horita, Hideomi Yamada, Bruno A Bergmans, Eric Legius, Florence Riant, Peter De Jonghe, Yuehong Li, Takashi Sekine, Takashi Igarashi, Ichiro Fujimoto, Katsuhiko Mikoshiba, Mitsunobu Shimadzu, Masaaki Shiohara, Nancy Braverman, Lihadh Al-Gazali, Toshiro Fujita, George Seki
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  ABSTRACT: Homozygous mutations in SLC4A4, encoding the electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1, have been known to cause proximal renal tubular acidosis (pRTA) and ocular abnormalities. In this study, we report two sisters with pRTA, ocular abnormalities, and hemiplegic migraine. Genetic analysis ruled out pathological mutations in the known genes for familial hemiplegic migraine, but identified a homozygous 65-bp deletion (Delta65bp) in the C terminus of NBCe1, corresponding to the codon change S982NfsX4. Several heterozygous members of this family also presented glaucoma and migraine with or without aura. Despite the normal electrogenic activity in Xenopus oocytes, the Delta65bp mutant showed almost no transport activity due to a predominant cytosolic retention in mammalian cells. Furthermore, coexpression experiments uncovered a dominant negative effect of the mutant through hetero-oligomer formation with wild-type NBCe1. Among other pRTA pedigrees with different NBCe1 mutations, we identified four additional homozygous patients with migraine. The immunohistological and functional analyses of these mutants demonstrate that the near total loss of NBCe1 activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH.
  Proceedings of the National Academy of Sciences 09/2010; 107(36):15963-8. · 9.68 Impact Factor
• Article: Arachidonic acid metabolites inhibit the stimulatory effect of angiotensin II in renal proximal tubules.

  Yuehong Li, Hideomi Yamada, Yoshihiro Kita, Masashi Suzuki, Yoko Endo, Shoko Horita, Osamu Yamazaki, Takao Shimizu, George Seki, Toshiro Fujita
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  ABSTRACT: Angiotensin II (Ang II) regulates renal proximal transport in a biphasic way via Ang II type 1 receptor (AT1). Whereas extracellular signal-regulated kinase (ERK) activation mediates the stimulatory effect, cytosolic phospholipase A2 (cPLA2) mediates the inhibitory effect independently of ERK. In this study, we tested the hypothesis that the cPLA2/P450 epoxygenase pathway might work to suppress the Ang II-mediated ERK activation. In the presence of arachidonic acid or 5,6-epoxyeicosatrienoic acid (EET), Ang II failed to stimulate the Na-HCO3 cotransporter activity in renal proximal tubules isolated from wild-type, AT1A-deficient, and cPLA2-alpha-deficient mice. In addition, Ang II failed to induce a significant ERK phosphorylation in the presence of arachidonic acid or 5,6-EET. Arachidonic acid or 5,6-EET also suppressed the stimulatory effect of Ang II on net proximal tubule bicarbonate absorption without changing cell Ca2+ concentrations. These results indicate that the cPLA2-alpha/P450/EET pathway blocks the stimulatory effect of Ang II by suppressing the ERK activation. Thus, the cPLA2-alpha/P450/EET pathway may operate as a unique negative feedback mechanism to attenuate excessive Ang II activity in the renal proximal tubules, where extremely high concentrations of Ang II are found.
  Hypertension Research 01/2009; 31(12):2155-64. · 2.58 Impact Factor
• Article: The Roles of Abnormal Renal Sodium Handling in Hypertension Associated with Metabolic Syndrome

  George Seki, Hideomi Yamada, Yuehong Li, Shoko Horita, Masashi Suzuki, Toshiro Fujita
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  ABSTRACT: There is an epidemic of the metabolic syndrome across the world, which is often associated with hypertension and other coronary risk factors. Insulin resistance is thought to play a key role in this condition. Several different mechanisms such as activation of renin-angiotensin system, enhancement of sympathetic nerve system, and hyperinsulinemia may underlie hypertension in metabolic syndrome. Unlike in other tissues, angiotensin II regulates renal proximal tubule transport in a biphasic manner. The molecular mechanism for the angiotensin II-mediated regulation of renal proximal transport has been recently clarified. On the other hand, insulin stimulates sodium transport in several nephron segments including proximal tubules. Recent data have shown that the sodium-retaining effect of insulin is paradoxically preserved in a mouse model of insulin resistance, which may be enhanced by sympathetic nerve activation. In this review, we will focus on the roles of abnormal renal proximal tubule sodium handling in hypertension.
  Current Hypertension Reviews 07/2008; 4(3):197-202.
• Article: Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na+-HCO3(-) transport.

  Yuehong Li, Hideomi Yamada, Yoshihiro Kita, Motoei Kunimi, Shoko Horita, Masashi Suzuki, Yoko Endo, Takao Shimizu, George Seki, Toshiro Fujita
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  ABSTRACT: Regulation of renal proximal transport by angiotensin II (Ang II) is biphasic: low concentrations (picomolar to nanomolar) stimulate reabsorption, but higher concentrations (nanomolar to micromolar) inhibit reabsorption. Traditionally, the stimulatory effect has been attributed to activation of protein kinase C and/or a decrease in intracellular cAMP, whereas the inhibitory action has been attributed to the activation of phospholipase A2 (PLA2) and the subsequent release of arachidonic acid. The Ang II receptor subtype responsible for these effects and the intracellular signaling pathways involved are not completely understood. We isolated proximal tubules from wild-type, Ang II type 1A receptor (AT1A)-deficient, and group IVA cytosolic phospholipase A2 (cPLA2alpha)-deficient mice, and compared their responses to Ang II. In wild-type mice, we found that the stimulatory and inhibitory effects of Ang II on Na+-HCO3(-) cotransporter activity are both AT1-mediated but that ERK activation only plays a role in the former. The stimulatory effect of Ang II was also observed in AT1A-deficient mice, suggesting that this occurs through AT1B. In contrast, the inhibitory effects of Ang II appeared to be mediated by cPLA2alpha activation because high-concentration Ang II stimulated Na+-HCO3(-) cotransporter activity when cPLA2alpha activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA2alpha/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA2alpha in a concentration-dependent manner via AT1, and that the balance between ERK and cPLA2alpha activities determines the ultimate response to Ang II in intact proximal tubules.
  Journal of the American Society of Nephrology 03/2008; 19(2):252-9. · 9.66 Impact Factor
• Article: Functional analysis of a novel missense NBC1 mutation and of other mutations causing proximal renal tubular acidosis.

  Masashi Suzuki, Maria Helena Vaisbich, Hideomi Yamada, Shoko Horita, Yuehong Li, Takashi Sekine, Nobuo Moriyama, Takashi Igarashi, Yoko Endo, Thaís P Cardoso, Luis Carlos F de Sá, Vera H Koch, George Seki, Toshiro Fujita
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  ABSTRACT: Mutations in the Na(+)-HCO(3)(-) cotransporter NBC1 cause severe proximal tubular acidosis (pRTA) associated with ocular abnormalities. Recent studies have suggested that at least some NBC1 mutants show abnormal trafficking in the polarized cells. This study identified a new homozygous NBC1 mutation (G486R) in a patient with severe pRTA. Functional analysis in Xenopus oocytes failed to detect the G486R activity due to poor surface expression. In ECV304 cells, however, G486R showed the efficient membrane expression, and its transport activity corresponded to approximately 50% of wild-type (WT) activity. In Madin-Darby canine kidney (MDCK) cells, G486R was predominantly expressed in the basolateral membrane domain as observed for WT. Among the previously identified NBC1 mutants that showed poor surface expression in oocytes, T485S showed the predominant basolateral expression in MDCK cells. On the other hand, L522P was exclusively retained in the cytoplasm in ECV304 and MDCK cells, and functional analysis in ECV304 cells failed to detect its transport activity. These results indicate that G486R, like T485S, is a partial loss of function mutation without major trafficking abnormalities, while L522P causes the clinical phenotypes mainly through its inability to reach the plasma membranes. Multiple experimental approaches would be required to elucidate potential disease mechanism by NBC1 mutations.
  Pflügers Archiv - European Journal of Physiology 02/2008; 455(4):583-93. · 4.46 Impact Factor