Highlights • Genetic dissection of ENaC mediated sodium transport validate novel drug targets. • Signaling pathways controlling ENaC activity identifies novel drug targets. • Phamacodynamic and ...pharmacokinetics properties of next generation diuretics.
Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the ...evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases. In animals, the control of an extracellular compartment was achieved by the emergence of multicellular organisms able to produce tight epithelial barriers creating a stable extracellular milieu. Finally, the adaptation to a terrestrian environment was achieved by the evolution of distinct regulatory pathways allowing salt and water conservation. In this review we emphasize the critical and dual role of Na(+)-K(+)-ATPase in the control of the ionic composition of the extracellular fluid and the renin-angiotensin-aldosterone system (RAAS) in salt and water conservation in vertebrates. The action of aldosterone on transepithelial sodium transport by activation of the epithelial sodium channel (ENaC) at the apical membrane and that of Na(+)-K(+)-ATPase at the basolateral membrane may have evolved in lungfish before the emergence of tetrapods. Finally, we discuss the implication of RAAS in the origin of the present pandemia of hypertension and its associated cardiovascular diseases.
Hypertension affects over 1.2 billion individuals worldwide and has become the most critical and expensive public health problem. Hypertension is a multifactorial disease involving environmental and ...genetic factors together with risk-conferring behaviors. The cause of the disease is identified in ∼10% of the cases (secondary hypertension), but in 90% of the cases no etiology is found (primary or essential hypertension). For this reason, a better understanding of the mechanisms controlling blood pressure in normal and hypertensive patients is the aim of very active experimental and clinical research. In this article, we review the importance of the renin-angiotensin-aldosterone system (RAAS) for the control of blood pressure, focusing on the evolution of the system and its critical importance for adaptation of vertebrates to a terrestrial and dry environment. The evolution of blood pressure control during the evolution of primates, hominins, and humans is discussed, together with the role of common genetic factors and the possible causes of the current hypertension pandemic in the light of evolutionary medicine.
In this review, we discuss genetic evidence supporting Guyton’s hypothesis stating that blood pressure control is critically depending on fluid handling by the kidney. The review is focused on the ...genetic dissection of sodium and potassium transport in the distal nephron and the collecting duct that are the most important sites for the control of sodium and potassium balance by aldosterone and angiotensin II. Thanks to the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, three main classes of diuretic receptors (furosemide, thiazide, amiloride) and the main components of the aldosterone- and angiotensin-dependent signaling pathways were molecularly identified over the past 20years. This will allow to design rational strategies for the treatment of hypertension and for the development of the next generation of diuretics.
The study of human monogenic diseases pseudohypoaldosteronism type 1 (PHA-1) and Liddle's syndrome as well as mouse models mimicking the salt-losing syndrome (PHA-1) or salt-sensitive hypertension ...(Liddle's syndrome) have established the epithelial sodium channel ENaC as a limiting factor in vivo in the control of ionic composition of the extracellular fluid, regulation of blood volume and blood pressure, lung alveolar clearance, and airway mucociliary clearance. In this review, we discuss more specifically the activation of ENaC by serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases are of critical importance in the activation of ENaC in different organs, such as the kidney, the lung, or the cochlea. Progress in understanding the basic mechanism of proteolytic activation of ENaC is accelerating, but uncertainty about the most fundamental aspects persists, leaving numerous still-unanswered questions.
Vertebrates control the osmolality of their extra- and intra-cellular compartments despite large variations in salt and water intake. Aldosterone-dependent sodium reabsorption and ...vasopressin-dependent water transport in the distal nephron and collecting duct play a critical role in the final control of sodium and water balance. Long-term fasting (no eating, no drinking) represents an osmotic challenge for survival. Evolution has found very different solutions to meet this challenge. To illustrate this point, I will discuss osmoregulation of a mammal (elephant seal pup) and of a fish (lungfish) that are able to survive long-term fasting for months or even years. Homer W. Smith taught us how informative comparative anatomy and physiology of the kidney could help physiologists and nephrologists to better understand how the kidney works. In recent years, comparative genomics, transcriptomics and proteomics across the tree of life have led to the emergence of a new discipline, evolutionary medicine. In the near future, physiologists and nephrologists will benefit from this new field of investigation, thanks to its potential for the identification of novel drug targets and therapies.
The amiloride-sensitive epithelial sodium channel (ENaC) and the thiazide-sensitive sodium chloride cotransporter (NCC) are key regulators of sodium and potassium and colocalize in the late distal ...convoluted tubule of the kidney. Loss of the
ENaC subunit leads to a perinatal lethal phenotype characterized by sodium loss and hyperkalemia resembling the human syndrome pseudohypoaldosteronism type 1 (PHA-I). In adulthood, inducible nephron-specific deletion of
ENaC in mice mimics the lethal phenotype observed in neonates, and as in humans, this phenotype is prevented by a high sodium (HNa
)/low potassium (LK
) rescue diet. Rescue reflects activation of NCC, which is suppressed at baseline by elevated plasma potassium concentration. In this study, we investigated the role of the
ENaC subunit in the PHA-I phenotype. Nephron-specific
ENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking
ENaC or
ΕΝaC, an HNa
/LK
diet did not normalize plasma potassium (K
) concentration or increase NCC activation. However, when K
was eliminated from the diet at the time that
ENaC was deleted, plasma K
concentration and NCC activity remained normal, and progressive weight loss was prevented. Loss of the late distal convoluted tubule, as well as overall reduced
ENaC subunit expression, may be responsible for the more severe hyperkalemia. We conclude that plasma K
concentration becomes the determining and limiting factor in regulating NCC activity, regardless of Na
balance in
ENaC-deficient mice.
Aldosterone and corticosterone bind to mineralocorticoid (MR) and glucocorticoid receptors (GR), which, upon ligand binding, are thought to translocate to the cell nucleus to act as transcription ...factors. Mineralocorticoid selectivity is achieved by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that inactivates 11β-hydroxy glucocorticoids. High expression levels of 11β-HSD2 characterize the aldosterone-sensitive distal nephron (ASDN), which comprises the segment-specific cells of late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). We used MR- and GR-specific antibodies to study localization and regulation of MR and GR in kidneys of rats with altered plasma aldosterone and corticosterone levels. In control rats, MR and GR were found in cell nuclei of thick ascending limb (TAL), DCT, CNT, CD cells, and intercalated cells (IC). GR was also abundant in cell nuclei and the subapical compartment of proximal tubule (PT) cells. Dietary NaCl loading, which lowers plasma aldosterone, caused a selective removal of GR from cell nuclei of 11β-HSD2-positive ASDN. The nuclear localization of MR was unaffected. Adrenalectomy (ADX) resulted in removal of MR and GR from the cell nuclei of all epithelial cells. Aldosterone replacement rapidly relocated the receptors in the cell nuclei. In ASDN cells, low-dose corticosterone replacement caused nuclear localization of MR, but not of GR. The GR was redistributed to the nucleus only in PT, TAL, early DCT, and IC that express no or very little 11β-HSD2. In ASDN cells, nuclear GR localization was only achieved when corticosterone was replaced at high doses. Thus ligand-induced nuclear translocation of MR and GR are part of MR and GR regulation in the kidney and show remarkable segment- and cell type-specific characteristics. Differential regulation of MR and GR may alter the level of heterodimerization of the receptors and hence may contribute to the complexity of corticosteroid effects on ASDN function.
Aldosterone promotes electrogenic sodium reabsorption through the amiloride-sensitive epithelial sodium channel (ENaC). Here, we investigated the importance of ENaC and its positive regulator ...channel-activating protease 1 (CAP1/Prss8) in colon. Mice lacking the αENaC subunit in colonic superficial cells (Scnn1a(KO)) were viable, without fetal or perinatal lethality. Control mice fed a regular or low-salt diet had a significantly higher amiloride-sensitive rectal potential difference (∆PDamil) than control mice fed a high-salt diet. In Scnn1a(KO) mice, however, this salt restriction-induced increase in ∆PDamil did not occur, and the circadian rhythm of ∆PDamil was blunted. Plasma and urinary sodium and potassium did not change with regular or high-salt diets or potassium loading in control or Scnn1a(KO) mice. However, Scnn1a(KO) mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention. Mice lacking the CAP1/Prss8 in colonic superficial cells (Prss8(KO)) were viable, without fetal or perinatal lethality. Compared with controls, Prss8(KO) mice fed regular or low-salt diets exhibited significantly reduced ∆PDamil in the afternoon, but the circadian rhythm was maintained. Prss8(KO) mice fed a low-salt diet also exhibited sodium loss through feces and higher plasma aldosterone levels. Thus, we identified CAP1/Prss8 as an in vivo regulator of ENaC in colon. We conclude that, under salt restriction, activation of the renin-angiotensin-aldosterone system in the kidney compensated for the absence of ENaC in colonic surface epithelium, leading to colon-specific pseudohypoaldosteronism type 1 with mineralocorticoid resistance without evidence of impaired potassium balance.
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