In Primary Aldosteronism, Mineralocorticoids Influence Exosomal Sodium-Chloride Cotransporter Abundance

Wolley, Martin; Wu, Aihua; Xu, Shengxin; Gordon, Richard D.; Fenton, Robert A.; Stowasser, Michael

doi:10.1681/asn.2015111221

Cited by 58 publications

(67 citation statements)

References 32 publications

(34 reference statements)

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“…An outcome of these studies is the ability to discern differences in the omics composition of urinary extracellular vesicles, correlate observed differences to health and acute or chronic renal disease, and use these observations to develop testable hypotheses addressing disease-specific mechanisms 74,118,130,132,133,169,170 . Furthermore, the utilization in these studies of second morning voids and spot urine samples to yield reproducible data suggests that the future for urinary extracellular vesicle diagnostics is encouraging.…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery

et al. 2017

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Urine is a valuable diagnostic medium and, with the discovery of urinary extracellular vesicles, is viewed as a dynamic bioactive fluid. Extracellular vesicles are lipid-enclosed structures that can be classified into three categories: exosomes, microvesicles (or ectosomes) and apoptotic bodies. This classification is based on the mechanisms by which membrane vesicles are formed: fusion of multivesicular bodies with the plasma membranes (exosomes), budding of vesicles directly from the plasma membrane (microvesicles) or those shed from dying cells (apoptotic bodies). During their formation, urinary extracellular vesicles incorporate various cell-specific components (proteins, lipids and nucleic acids) that can be transferred to target cells. The rigour needed for comparative studies has fueled the search for optimal approaches for their isolation, purification, and characterization. RNA, the newest extracellular vesicle component to be discovered, has received substantial attention as an extracellular vesicle therapeutic, and compelling evidence suggests that ex vivo manipulation of microRNA composition may have uses in the treatment of kidney disorders. The results of these studies are building the case that urinary extracellular vesicles act as mediators of renal pathophysiology. As the field of extracellular vesicle studies is burgeoning, this Review focuses on primary data obtained from studies of human urine rather than on data from studies of laboratory animals or cultured immortalized cells.

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Section: Discussionmentioning

confidence: 99%

Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery

et al. 2017

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“…The CDNOS1KO mice presented with significantly higher fasting plasma potassium levels on an NS diet. In humans, mineralocorticoids (ie, fludrocortisone) lead to an increase in NCC and NCC phosphorylation via potassium regulation, and aldosterone promotes ENaC‐dependent sodium reabsorption. Similarly, in rats, AngII infusion leads to an increase in ENaC activation and unregulated potassium secretion (as reflected by a significant reduction in plasma potassium) that secondarily stimulates NCC activity .…”

Section: Discussionmentioning

confidence: 99%

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

Hyndman

Mironova

Giani

et al. 2017

JAHA

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BackgroundDuring high sodium intake, the renin‐angiotensin‐aldosterone system is downregulated and nitric oxide signaling is upregulated in order to remain in sodium balance. Recently, we showed that collecting duct nitric oxide synthase 1β is critical for fluid‐electrolyte balance and subsequently blood pressure regulation during high sodium feeding. The current study tested the hypothesis that high sodium activation of the collecting duct nitric oxide synthase 1β pathway is critical for maintaining sodium homeostasis and for the downregulation of the renin‐angiotensin‐aldosterone system–epithelial sodium channel axis.Methods and ResultsMale control and collecting duct nitric oxide synthase 1β knockout (CDNOS1KO) mice were placed on low, normal, and high sodium diets for 1 week. In response to the high sodium diet, plasma sodium was significantly increased in control mice and to a significantly greater level in CDNOS1KO mice. CDNOS1KO mice did not suppress plasma aldosterone in response to the high sodium diet, which may be partially explained by increased adrenal AT1R expression. Plasma renin concentration was appropriately suppressed in both genotypes. Furthermore, CDNOS1KO mice had significantly higher intrarenal angiotensin II with high sodium diet, although intrarenal angiotensinogen levels and angiotensin‐converting enzyme activity were similar between knockout mice and controls. In agreement with inappropriate renin‐angiotensin‐aldosterone system activation in the CDNOS1KO mice on a high sodium diet, epithelial sodium channel activity and sodium transporter abundance were significantly higher compared with controls.ConclusionsThese data demonstrate that high sodium activation of collecting duct nitric oxide synthase 1β signaling induces suppression of systemic and intrarenal renin‐angiotensin‐aldosterone system, thereby modulating epithelial sodium channel and other sodium transporter abundance and activity to maintain sodium homeostasis.

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“…The measurement of urinary exosomal NCC is currently being used for the estimation of various renal functions, as reported recently [23] . What do our data teach us about the mechanism of production of KLHL3-induced dominant versus recessive disease?…”

Section: Discussionmentioning

confidence: 99%

Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter

Bassat

Carmon²,

Hanukoglu³

et al. 2017

Nephron

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Background: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described. Methods: Clinical and genetic investigation of members of 2 families was performed, one with recessive FHHt, and the other, an expansion of a family with Q309R KLHL3 dominant mutation, previously reported by us. Urinary exosomal sodium chloride cotransporter (NCC) was measured. Results: A family with recessive FHHt caused by a new KLHL3 mutation, S553L, is described. This consanguineous Jewish family of Yemenite extraction, included 2 homozygous and 7 heterozygous affected subjects. Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation. In the recessive S553L family, homozygotes appeared to have increased urinary NCC abundance. Surprisingly, heterozygotes seemed to have also increased urinary NCC, though at an apparently lower degree. This was not accompanied by a clinical phenotype. Conclusions: A new recessive mutation in KLHL3 (S553L) was identified in FHHt. Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form. Unexpectedly, in the recessive disease, heterozygotes seemed to have increased urinary NCC as well, apparently not sufficient quantitatively to produce a clinical phenotype.

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In Primary Aldosteronism, Mineralocorticoids Influence Exosomal Sodium-Chloride Cotransporter Abundance

Cited by 58 publications

References 32 publications

Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery

Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery

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

Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter

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