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
Summary
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]
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