Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Gao, Yang; Stuart, Deborah; Takahishi, Takamune; Kohan, Donald E.

doi:10.1161/jaha.118.009236

Cited by 21 publications

(16 citation statements)

References 34 publications

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“…This result is partly consistent with a previous study on nephron-specific disruption of NOS3 in mice, in which p-NCC and total NCC, but not ENaC, were elevated in NOS3 knockout mice after 4 hours of an acute 3.2% Na þ load. 28 In this study they disrupted NOS3 in the whole nephron, and NOS1 and 2 were preserved. In our study, whole NOSs were inhibited by L-NAME and could induce sustained high oxidative stress to activate NCC phosphorylation by the SPAK-oxidative stress-responsive kinase 1 (OSR) pathway.…”

Section: Discussionmentioning

confidence: 49%

Low-dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents

Wang

Kawakami-Mori

Liu

et al. 2020

Kidney International

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To investigate the cause of salt sensitivity in a normotensive animal model, we treated rats with a low-dose of the nitric oxide synthase inhibitor, L-NAME, that does not elevate blood pressure per se or induce kidney fibrosis. A high salt diet increased the circulating blood volume both in L-NAMEtreated and nontreated animals for the first 24 hours. Thereafter, the blood volume increase persisted only in the L-NAME-treated rats. Blood pressure was higher in the L-NAMEtreated group from the start of high salt diet exposure. Within the first 24 hours of salt loading, the L-NAME treated animals failed to show vasodilation and maintained high systemic vascular resistance in response to blood volume expansion. After four weeks on the high salt diet, the slope of the pressure-natriuresis curve was blunted in the L-NAME-treated group. An increase in natriuresis was observed after treatment with hydrochlorothiazide, but not amiloride, a change observed in parallel with increased phosphorylated sodium-chloride cotransporter (NCC). In contrast, a change in blood pressure was not observed in L-NAME-treated NCCdeficient mice fed a high salt diet. Moreover, direct L-NAMEinduced NCC activation was demonstrated in cells of the mouse distal convoluted tubule. The vasodilatator, sodium nitroprusside, downregulated phosphorylated NCC expression. The effect of L-NAME on phosphorylated NCC was blocked by both the SPAK inhibitor STOCK2S-26016 and the superoxide dismutase mimetic TEMPO which also attenuated salt-induced hypertension. These results suggest that the initiation of salt sensitivity in normotensive rodents could be due to hyporeactivity of the vasculature and that maintaining blood pressure could result in a high circulating volume due to inappropriate NCC activity in the low-dose L-NAME model. Thus, even slightly impaired nitric oxide production may be important in salt sensitivity regulation in healthy rodents.

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Section: Discussionmentioning

confidence: 49%

Low-dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents

Wang

Kawakami-Mori

Liu

et al. 2020

Kidney International

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“…We were able to replicate this association using only the QTPhenProxy method on the UK Biobank, and not traditional binary trait analysis. NOS3 has been shown to be related to hypertension either through salt excretion regulation in the kidney (Gao Yang et al, 2018) or regulation of vascular relaxation in endothelial cells (Farah et al, 2018). Other discovered genes by QTPhenProxy are also associated with related cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Medical data and machine learning improve power of stroke genome-wide association studies

Gisladottir

Tatonetti

2020

Preprint

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Genome-wide association studies (GWAS) may require enrollment of up to millions of participants to power variant discovery. This requires manual curation of cases and controls with large-scale collaborations. Biobanks connected to electronic health records (EHR) can facilitate these studies by using data from clinical care systems, like billing diagnosis codes, as phenotypes. These systems, however, do not de ne adjudicated cases and controls. Machine learning can add nuance to these de nitions. We developed QTPhenProxy, a machine learning model that assigns everyone in a cohort a probability of having the study disease, and then run a GWAS using the probabilities as a quantitative trait. With an order of magnitude fewer cases than the largest stroke GWAS, our method outperformed previous methods at replicating known variants in stroke and discovered a novel variant in ABCG8 associated with intracerebral hemorrhage in the UK Biobank.QTPhenProxy expands traditional phenotyping to improve the power of GWAS.

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“…Though flow-mediated Na absorption prevents renal Na losses, flow mediated paracrine factors are stimulated to inhibit Na absorption and enhance Na excretion. These factors include nitric oxide (NO), endothelin-1 (ET1), nucleotides, prostanoids, and heme oxygenase-1 (HO1) ( Rieg et al, 2007 ; Lyon-Roberts et al, 2011 ; Flores et al, 2012 ; Liu et al, 2015 ; Pandit et al, 2015 ; Gao et al, 2018 ; Repetti et al, 2019 ). Therefore, net Na excretion from each segment represents a balance of flow-mediated Na absorption vs. flow-mediated paracrine molecules that antagonize Na transport ( Flores et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Unilateral Nephrectomy Stimulates ERK and Is Associated With Enhanced Na Transport

et al. 2021

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Nephron loss initiates compensatory hemodynamic and cellular effects on the remaining nephrons. Increases in single nephron glomerular filtration rate and tubular flow rate exert higher fluid shear stress (FSS) on tubules. In principal cell (PC) culture models FSS induces ERK, and ERK is implicated in the regulation of transepithelial sodium (Na) transport, as well as, proliferation. Thus, we hypothesize that high tubular flow and FSS mediate ERK activation in the cortical collecting duct (CCD) of solitary kidney which regulates amiloride sensitive Na transport and affects CCD cell number. Immunoblotting of whole kidney protein lysate was performed to determine phospho-ERK (pERK) expression. Next, sham and unilateral nephrectomized mice were stained with anti-pERK antibodies, and dolichos biflorus agglutinin (DBA) to identify PCs with pERK. Murine PCs (mpkCCD) were grown on semi-permeable supports under static, FSS, and FSS with U0126 (a MEK1/2 inhibitor) conditions to measure the effects of FSS and ERK inhibition on amiloride sensitive Na short circuit current (Isc). pERK abundance was greater in kidney lysate of unilateral vs. sham nephrectomies. The total number of cells in CCD and pERK positive PCs increased in nephrectomized mice (9.3 ± 0.4 vs. 6.1 ± 0.2 and 5.1 ± 0.5 vs. 3.6 ± 0.3 cell per CCD nephrectomy vs. sham, respectively, n > 6 per group, p < 0.05). However, Ki67, a marker of proliferation, did not differ by immunoblot or immunohistochemistry in nephrectomy samples at 1 month compared to sham. Next, amiloride sensitive Isc in static mpkCCD cells was 25.3 ± 1.7 μA/cm2 (n = 21), but after exposure to 24 h of FSS the Isc increased to 41.4 ± 2.8 μA/cm2 (n = 22; p < 0.01) and returned to 19.1 ± 2.1 μA/cm2 (n = 18, p < 0.01) upon treatment with U0126. Though FSS did not alter α- or γ-ENaC expression in mpkCCD cells, γ-ENaC was reduced in U0126 treated cells. In conclusion, pERK increases in whole kidney and, specifically, CCD cells after nephrectomy, but pERK was not associated with active proliferation at 1-month post-nephrectomy. In vitro studies suggest high tubular flow induces ERK dependent ENaC Na absorption and may play a critical role in Na balance post-nephrectomy.

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Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Cited by 21 publications

References 34 publications

Low-dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents

Low-dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents

Medical data and machine learning improve power of stroke genome-wide association studies

Unilateral Nephrectomy Stimulates ERK and Is Associated With Enhanced Na Transport

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