Abstract

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.

Highlights

  • Autosomal dominant polycystic kidney disease (ADPKD) has a population prevalence of 1:1000 and is the most common monogenic cause of kidney failure in adults [1, 2]

  • Evidence accumulated over the last 20 years has shown that the systemic bioavailability of nitric oxide (NO) is impaired in ADPKD

  • Apart from its known effects in mediating endothelial dysfunction, hypertension, and exercise capacity, it has been shown to mediate kidney cyst growth [13, 23, 45,46,47]. We investigated this hypothesis further, and identified three novel findings: (i) firstly, intracellular levels of NO, using a direct method of measurement, was markedly reduced in human ADPKD cell lines; (ii) secondly, L-arginine and sodium nitroprusside reduced cyst diameter in vitro, confirming that modulation of NO has direct effects on cyst growth; (iii) thirdly, despite previous evidence supporting the beneficial effects of dietary nitrates in non-renal chronic disease models [20, 21, 48], the continuous administration of sodium nitrate for 8 months, regardless of dosage, did not alter the progression of cyst growth in Pkd1RC/RC mice

Read more

Summary

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) has a population prevalence of 1:1000 and is the most common monogenic cause of kidney failure in adults [1, 2]. It is caused by loss-of-function variants in either PKD1 or PKD2, which encode the trans-membranous, polycystin-1 and 2 proteins, respectively [3]. The formation of expansile cysts which compress surrounding healthy renal parenchyma leads to late-onset kidney failure, and this, together with cardiovascular disease (hypertension, heart and valvular abnormalities and vascular aneurysms), results in premature death in patients with ADPKD [3,4,5]. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, a pan-NOS inhibitor) had more consistent findings and resulted in exacerbation of cystic kidney disease and hypertension [13, 15]

Objectives
Methods
Results
Conclusion

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.