Regulation of fluid reabsorption in rat or mouse proximal renal tubules by asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase 1

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
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 > Institute of Cardiovascular and Medical Sciences
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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