Protein kinase D2 regulates epithelial sodium channel activity and aldosterone non-genomic responses in renal cortical collecting duct cells

Thomas, Warren; Dooley, Ruth; Quinn, Sinéad; Robles, Manuel Yusef; Harvey, Bill

doi:10.1016/j.steroids.2019.108553

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…While we inhibited MR using spironolactone, aldosterone was still present at elevated levels and can stimulate ENaC apical expression. 50 However, we did not observe increased ENaC γ subunit apical localization with BDL after spironolactone treatment. BDL will also increase renal tubular concentrations of other compounds, e.g., conjugated bilirubin, as tubular and urinary bilirubin precipitates suggest tubular concentrations can be high.…”

Section: Discussioncontrasting

confidence: 69%

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice

Wang,

Mutchler,

Carrisoza-Gáytan

et al. 2023

Preprint

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Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone dives Na+ retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na+ channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K+] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na+ absorption but had no effect on K+ secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients.

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Section: Discussioncontrasting

confidence: 69%

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice

Wang,

Mutchler,

Carrisoza-Gáytan

et al. 2023

Preprint

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Regulating distal nephron functions and salt sensitivity

Ueda,

Shimosawa

2024

American Journal of Physiology-Renal Physiology

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This review highlights the molecular basis of salt sensitivity in hypertension, with a focus on the regulation of sodium transport in the distal nephron. Sodium reabsorption in this region is often linked to the actions of aldosterone, although in recent years numerous findings have been reported on the aldosterone-independent pathway of acquiring salt sensitivity by potassium deficiency or potassium loading. The key to this discussion is the interplay, through extracellular potassium concentration, between the first part of the tubules expressing the Na+-Cl- cotransporter (NCC) and the second part expressing the epithelial sodium channel (ENaC). The molecular pathways such as WNK-SPAK/OSR1 signaling, KLHL3-CUL3 complex, protein phosphatases and mTORC2-Nedd4L pathway are described as the mechanism by which salt sensitivity on blood pressure is acquired in response to changes in physiological conditions including potassium depletion or loading. This review highlights the potential for targeting these molecular pathways to develop novel therapeutic strategies for the treatment of salt-sensitive hypertension, the mechanism of which remains to be elucidated.

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Sex Differences in Kidney Health and Disease

Harvey,

Alvarez de la Rosa

2024

Nephron

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Background: Sex differences exist in kidney physiology and disease which are underpinned by the biological actions of the sex hormones estrogen, progesterone and testosterone. In this review, we present an up-to-date discussion of the hormonal and molecular signalling pathways implicated in sex differences in kidney health and disease. Summary: Estrogen and progesterone have protective effects on renal blood flow, glomerular filtration rate and nephron ion and water reabsorptive processes, whereas testosterone tends to compromise these functions. The biological effects of estrogen appear to be the most important in reinforcing kidney function and protecting against kidney diseases in females. The actions of estrogen are myriad but all tend to bolster kidney physiology to maintain a steady-state and adaptable extracellular fluid volume (ECFV) and blood pressure. Estrogen safeguards ECFV homeostasis by stimulating renal epithelial sodium channel (ENaC) and water channel (AQP2) expression and transport function. Renal maintenance of ECFV within narrow physiological limits is a first-line of defense against hypertension and lowers the risk of cardiovascular disease in women. The estrogenic and XX chromosome basis for a female advantage are evident in a wide range of kidney diseases including acute kidney injury, chronic kidney disease, end-stage kidney disease, diabetic kidney disease, and polycystic kidney disease. The molecular mechanisms involve estrogen regulation of nephron ion and water transport, genetic immunogenic responses, activation of the protective arm of the renin angiotensin-aldosterone system and XX chromosome reinforcement of immune responses. Kidney disease can also predispose patients to cancer and women are protected in renal cancer with lower incidence, morbidity, and mortality than age-matched men with the disease. Key Messages: This review underscores the importance of incorporating sex-specific considerations into clinical practice and basic research to bridge the gap in understanding and addressing biological sex disparities in kidney disease and renal cancer.

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Protein kinase D2 regulates epithelial sodium channel activity and aldosterone non-genomic responses in renal cortical collecting duct cells

Cited by 3 publications

References 48 publications

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice

Regulating distal nephron functions and salt sensitivity

Sex Differences in Kidney Health and Disease

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