Bell, T., Araujo, M., Luo, Z., Tomlinson, J., Leiper, J. , Welch, W. J. and Wilcox, C. S. (2018) Regulation of fluid reabsorption in rat or mouse proximal renal tubules by asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase 1. American Journal of Physiology: Renal Physiology, 315(1), F74-F78. (doi: 10.1152/ajprenal.00560.2017) (PMID:29513072) (PMCID:PMC6087787)
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Abstract
Nitric oxide prevents hypertension yet enhances proximal tubule Na+ reabsorption. Nitric oxide synthase is inhibited by asymmetric dimethylarginine (ADMA) that is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) whose type 1 isoform is expressed abundantly in the proximal tubule (PT). We hypothesize that ADMA metabolized by DDAH-1 inhibits fluid reabsorbtion (Jv) by the proximal tubule. S2 segments of the PT were microperfused between blocks in vivo to assess Jv in anesthetized rats. Compared with vehicle, microperfusion of ADMA or Nω-nitro-l-arginine methyl ester (l-NAME) in the proximal tubule reduced Jv dose dependently. At 10−4 mol/l both reduced Jv by ~40% (vehicle: 3.2 ± 0.7 vs. ADMA: 2.1 ± 0.5, P < 0.01 vs. l-NAME: 1.9 ± 0.4 nl·min−1·mm−1, P < 0.01; n = 10). Selective inhibition of DDAH-1 in rats with intravenous L-257 (60 mg/kg) given 2 h before and L-257 (10−5 mol/l) perfused in the proximal tubule for 5 min reduced Jv by 32 ± 4% (vehicle: 3.2 ± 0.5 vs. L-257: 2.2 ± 0.5 nl·min−1·mm−1; P < 0.01) and increased plasma ADMA by ≈50% (vehicle: 0.46 ± 0.03 vs. L-257: 0.67 ± 0.03 µmol/l, P < 0.0001) without changing plasma symmetric dimethylarginine. Compared with nontargeted control small-interference RNA, knock down of DDAH-1 in mice by 60% with targeted small-interference RNAs (siRNA) reduced Jv by 29 ± 5% (nontargeted siRNA: 2.8 ± 0.20 vs. DDAH-1 knockdown: 1.9 ± 0.31 nl·min−1·mm−1, P < 0.05). In conclusion, fluid reabsorption in the proximal tubule is reduced by tubular ADMA or by blocking its metabolism by DDAH-1. L-257 is a novel regulator of proximal tubule fluid reabsorption.
Item Type: | Articles |
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Additional Information: | This study was supported by National Institutes of Health Grants DK-49870, DK-109272, and HL-68686 to C. S. Wilcox and W. J. Welch and by funds from the George E. Schreiner Chair of Nephrology, the Georgetown Hypertension Center, and the Smith-Kogod Family Foundation. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Leiper, Professor James |
Authors: | Bell, T., Araujo, M., Luo, Z., Tomlinson, J., Leiper, J., Welch, W. J., and Wilcox, C. S. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | American Journal of Physiology: Renal Physiology |
Publisher: | American Physiological Society |
ISSN: | 1931-857X |
ISSN (Online): | 1522-1466 |
Published Online: | 01 July 2018 |
Copyright Holders: | Copyright © 2018 American Physiological Society |
First Published: | First published in American Journal of Physiology: Renal Physiology 315(1):F74-F78 |
Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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