Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways

Hyndman, Kelly A.; Mironova, Elena; Giani, Jorge F.; Dugas, Courtney; Collins, Jessika; McDonough, Alicia A.; Stockand, James D.; Pollock, Jennifer S.

doi:10.1161/jaha.117.006896

Cited by 21 publications

(27 citation statements)

References 50 publications

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“…It is likely that reduced local NO in the renal inner medulla further contributes to the upregulation of renin production by the principal cells of the CD, and ultimately intrarenal Ang II content. In collecting duct nitric oxide synthase 1β knockout (CDNOS1KO) mice under changes in dietary salt, CD renin does not change in renal medullary tissues (Hyndman et al, 2017). However, in CD-eNOS-deficient mice used in the present study, renin immunostaining in cortical and medullary renal CD cells was augmented but not in JG cells.…”

Section: Discussioncontrasting

confidence: 51%

Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct

et al. 2020

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In the kidney, the stimulation of renin production by the collecting duct (CD-renin) contributes to the development of hypertension. The CD is a major nephron segment for the synthesis of nitric oxide (NO), and low NO bioavailability in the renal medulla is associated with hypertension. However, it is unknown whether NO regulates renin production in the CD. To test the hypothesis that low intrarenal NO levels stimulate the production of CD-renin, we first examined renin expression in the distal nephron segments of CD-eNOS deficient mice. In these mice, specific CD-renin immunoreactivity was increased compared to wild-type littermates; however, juxtaglomerular (JG) renin was not altered. To further assess the intracellular mechanisms involved, we then treated M-1 cells with either 1 mM L-NAME (L-arginine analog), an inhibitor of NO synthase activity, or 1 mM NONOate, a NO donor. Both treatments increased intracellular renin protein levels in M-1 cells. However, only the inhibition of NOS with L-NAME stimulated renin synthesis and secretion as reflected by the increase in Ren1C transcript and renin protein levels in the extracellular media, respectively. In addition, NONOate induced a fast mobilization of cGMP and intracellular renin accumulation. These response was partially prevented by guanylyl cyclase inhibition with ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1]. Accumulation of intracellular renin was blocked by protein kinase G (PKG) and protein kinase C (PKC) inhibitors. Our data indicate that low NO bioavailability increases CD-renin synthesis and secretion, which may contribute to the activation of intrarenal renin angiotensin system.

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Section: Discussioncontrasting

confidence: 51%

Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct

et al. 2020

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“…However, it was also shown that NO could inhibit sodium reabsorption in isolated collecting duct preparations of rats [ 48 ]. These data were confirmed in vivo in mice lacking nNOS in the collecting duct which exhibited significantly higher sodium retention when kept on a high-salt diet compared to WT-mice [ 49 ]. These natriuretic effects of NO might be mediated also by other NO-synthases and also be sex-specific since it is only in female that collecting duct specific eNOS knockout mice, that the sodium and water secretion was impaired [ 50 ].…”

Section: Impact Of the Impaired No/sgc/cgmp Signaling On Kidney Fumentioning

confidence: 77%

The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective

Krishnan

Kraehling

Eitner

et al. 2018

IJMS

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Chronic Kidney Disease (CKD) is a highly prevalent disease with a substantial medical need for new and more efficacious treatments. The Nitric Oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine monophosphate (cGMP) signaling cascade regulates various kidney functions. cGMP directly influences renal blood flow, renin secretion, glomerular function, and tubular exchange processes. Downregulation of NO/sGC/cGMP signaling results in severe kidney pathologies such as CKD. Therefore, treatment strategies aiming to maintain or increase cGMP might have beneficial effects for the treatment of progressive kidney diseases. Within this article, we review the NO/sGC/cGMP signaling cascade and its major pharmacological intervention sites. We specifically focus on the currently known effects of cGMP on kidney function parameters. Finally, we summarize the preclinical evidence for kidney protective effects of NO-donors, PDE inhibitors, sGC stimulators, and sGC activators.

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“…For controls 1/20 males and 3/18 females had mild damage with 2 or fewer protein casts detected. At 13 ± 4 weeks of age, mice were fed a low-sodium diet (<0.01% NaCl) followed by a week of HSD (4.0% NaCl) following our previously published protocols ( 23 , 24 ). Urine flow was significantly higher in male i Hoxb7 Hdac1/2KO mice compared with littermate controls on all salt diets ( Figure 3B , Supplemental Table 7 ), but sodium excretion was similar between the genotypes ( Supplemental Table 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…Mice were provided gel diets with different amounts of NaCl as described in detail elsewhere ( 24 ) for both the metabolic cage and telemetry studies. Mice were individually housed in the metabolic cages as previously described ( 24 ). Following the metabolic cage study, mice underwent telemetry surgery as previously described ( 23 ).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, paracrine/autocrine, natriuretic, and diuretic factors, such as NO, are produced at the highest levels in the inner medullary collecting duct ( 21 , 22 ). Studies with collecting duct principal cell–specific NO system–knockout mice have provided compelling evidence that NO is critical for fluid-electrolyte balance and blood pressure control ( 23 , 24 ). Thus, HDACs in the renal medulla may be a critical site of regulation of these natriuretic factors.…”

Section: Introductionmentioning

confidence: 99%

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Fluid-electrolyte homeostasis requires histone deacetylase function

Hyndman¹,

Speed²,

Mendoza³

et al. 2020

JCI Insight

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Histone deacetylase (HDAC) enzymes regulate transcription through epigenetic modification of chromatin structure, but their specific functions in the kidney remain elusive. We discovered that the human kidney expresses class I HDACs. Kidney medulla-specific inhibition of class I HDACs in the rat during high-salt feeding results in hypertension, polyuria, hypokalemia, and nitric oxide deficiency. Three new inducible murine models were used to determine that HDAC1 and HDAC2 in the kidney epithelium are necessary for maintaining epithelial integrity and maintaining fluid-electrolyte balance during increased dietary sodium intake. Moreover, single-nucleus RNA-sequencing determined that epithelial HDAC1 and HDAC2 are necessary for expression of many sodium or water transporters and channels. In performing a systematic review and meta-analysis of serious adverse events associated with clinical HDAC inhibitor use, we found that HDAC inhibitors increased the odds ratio of experiencing fluid-electrolyte disorders, such as hypokalemia. This study provides insight on the mechanisms of potential serious adverse events with HDAC inhibitors, which may be fatal to critically ill patients. In conclusion, kidney tubular HDACs provide a link between the environment, such as consumption of high-salt diets, and regulation of homeostatic mechanisms to remain in fluid-electrolyte balance.

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Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways

Cited by 21 publications

References 50 publications

Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct

Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct

The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective

Fluid-electrolyte homeostasis requires histone deacetylase function

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