Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the express...

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Published in:	PloS one Vol. 16; no. 4; p. e0248400
Main Authors:	Zhang, Jennifer Q J, Saravanabavan, Sayanthooran, Cheng, Kai Man, Raghubanshi, Aarya, Chandra, Ashley N, Munt, Alexandra, Rayner, Benjamin, Zhang, Yunjia, Chau, Katrina, Wong, Annette T Y, Rangan, Gopala K
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 22-04-2021 Public Library of Science (PLoS)
Subjects:	Animal models Arginine Biology and Life Sciences Cysts Data analysis Deoxyribonucleic acid Diet Dietary supplements DNA DNA damage Drinking water Drug therapy Ecology and Environmental Sciences Editing Epithelial cells Epithelium Hospitals Hypertension Kidney diseases Kidney transplantation Kidneys Long-term effects Measurement methods Medical research Medicine Medicine and Health Sciences Methodology NG-Nitroarginine methyl ester Nitric oxide Nitric-oxide synthase Physical Sciences Physiological aspects Polycystic kidney Polycystic kidney disease Renal failure Research and Analysis Methods Reviews Single-nucleotide polymorphism Sodium nitroprusside Substrates Testing Visualization Australia United States > US New South Wales Australia
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Summary:	Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9-7, WT 9-12), and the effect of L-arginine on an in vitro model of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygous Pkd1RC/RC mice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.1, 1 or 10 mmol/kg/day), or sodium chloride (vehicle; 10 mmol/kg/day), supplemented drinking water from postnatal month 1 to 9 (n = 12 per group). In vitro, intracellular NO, as assessed by DAF-2/DA fluorescence, was reduced by >70% in human ADPKD cell lines, and L-arginine and the NO donor, sodium nitroprusside, both attenuated in vitro cyst growth by up to 18%. In contrast, in Pkd1RC/RC mice, sodium nitrate supplementation increased serum nitrate/nitrite levels by ~25-fold in the high dose group (P<0.001), but kidney enlargement and percentage cyst area was not altered, regardless of dose. In conclusion, L-arginine has mild direct efficacy on reducing renal cyst growth in vitro, whereas long-term sodium nitrate supplementation was ineffective in vivo. These data suggest that the bioconversion of dietary nitrate to NO by the entero-salivary pathway may not be sufficient to influence the progression of renal cyst growth in ADPKD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0248400