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NaHCO3 Dilates Mouse Afferent Arteriole Via Na+/HCO3- Cotransporters NBCs.

ABSTRACT: Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO3 dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na+/HCO3- cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 µmol/L), dilated 45±2% (n=6, P<0.05) in response to NaHCO3 (44 mmol/L). Whereas, NaCl solution containing the same Na+ concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2',7'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29±0.02 (n=6; P<0.05) in the presence of NaHCO3, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 ?M nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53±4% (n=7; P<0.005) and increases NO generation by 22±3% (n=7; P<0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO3 increased NO generation in Af-Art by 19±4% (n=5; P<0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9-10; P<0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO3-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO3 dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.

SUBMITTER: Jiang S

PROVIDER: S-EPMC6785401 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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NaHCO3 Dilates Mouse Afferent Arteriole Via Na+/HCO3- Cotransporters NBCs.

Jiang Shan S Wang Ximing X Wei Jin J Zhang Gensheng G Zhang Jie J Xie Peng P Xu Lan L Wang Lei L Zhao Liang L Li Lingli L Wilcox Christopher S CS Chen Jianghua J Lai En Yin EY Liu Ruisheng R

Hypertension (Dallas, Tex. : 1979) 20190916 5

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO3 dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na+/HCO3- cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolate ...[more]

PMID: 31522618

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Project description:Na-HCO3 cotransport (NBC) regulates intracellular pH (pHi) and HCO3 secretion in rat colon. NBC has been characterized as a 5,5'-diisothiocyanato-2-2'-stilbene (DIDS)-sensitive transporter in several tissues, while the colonic NBC is sensitive to both amiloride and DIDS. In addition, the colonic NBC has been identified as critical for pHi regulation as it is activated by intravesicular acid pH. Molecular studies have identified several characteristically distinct NBC isoforms [i.e. electrogenic (NBCe) and electroneutral (NBCn)] that exhibit tissue specific expression. This study was initiated to establish the molecular identity and specific function of NBC isoforms in rat colon. Northern blot and reverse transcriptase PCR (RT-PCR) analyses revealed that electrogenic NBCe1B or NBCe1C (NBCe1B/C) isoform is predominantly expressed in proximal colon, while electroneutral NBCn1C or NBCn1D (NBCn1C/D) is expressed in both proximal and distal colon. Functional analyses revealed that amiloride-insensitive, electrogenic, pH gradient-dependent NBC activity is present only in basolateral membranes of proximal colon. In contrast, amiloride-sensitive, electroneutral, [H(+)]-dependent NBC activity is present in both proximal and distal colon. Both electrogenic and electroneutral NBC activities are saturable processes with an apparent Km for Na of 7.3 and 4.3 mM, respectively; and are DIDS-sensitive with apparent Ki of 8.9 and 263.8 µM, respectively. In addition to Na-H exchanger isoform-1 (NHE1), pHi acidification is regulated by a HCO3-dependent mechanism that is HOE694-insensitive in colonic crypt glands. We conclude from these data that electroneutral, amiloride-sensitive NBC is encoded by NBCn1C/D and is present in both proximal and distal colon, while NBCe1B/C encodes electrogenic, amiloride-insensitive Na-HCO3 cotransport in proximal colon. We also conclude that NBCn1C/D regulates HCO3-dependent HOE694-insensitive Na-HCO3 cotransport and plays a critical role in pHi regulation in colonic epithelial cells.

Dataset Information

NaHCO3 Dilates Mouse Afferent Arteriole Via Na+/HCO3- Cotransporters NBCs.

Publications

NaHCO<sub>3</sub> Dilates Mouse Afferent Arteriole Via Na<sup>+</sup>/HCO<sub>3</sub><sup>-</sup> Cotransporters NBCs.

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