Extracellular Fluid Homeostasis Research Articles

Epithelial Na + Channels Function as Extracellular Sensors.

The epithelial Na + channel (ENaC) resides on the apical surfaces of specific epithelia in vertebrates and plays a critical role in extracellular fluid homeostasis. Evidence that ENaC senses the external environment emerged well before the molecular identity of the channel was reported three decades ago. This article discusses progress toward elucidating the mechanisms through which specific external factors regulate ENaC function, highlighting insights gained from structural studies of ENaC and related family members. It also reviews our understanding of the role of ENaC regulation by the extracellular environment in physiology and disease. After familiarizing the reader with the channel's physiological roles and structure, we describe the central role protein allostery plays in ENaC's sensitivity to the external environment. We then discuss each of the extracellular factors that directly regulate the channel: proteases, cations and anions, shear stress, and other regulators specific to particular extracellular compartments. For each regulator, we discuss the initial observations that led to discovery, studies investigating molecular mechanism, and the physiological and pathophysiological implications of regulation. © 2024 American Physiological Society. Compr Physiol 14:5407-5447, 2024.

Activation by Cleavage of the Epithelial Na+ Channel α and γ Subunits Independently Coevolved with the Vertebrate Terrestrial Migration

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel’s α and γ subunits. Here we investigated the evolution of ENaC regulatory mechanisms to determine which features coevolved with the marine‐terrestrial transition. We consistently found both activating cleavage sites in the ENaC α and γ subunits of terrestrial vertebrates, while they appeared only sporadically in fishes. We confirmed that cleavage occurred at sites found in the γ subunit from Australian lungfish, leading to channel activation. Phylogenetic analysis and likelihood ratio tests showed that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation. They also showed a coevolutionary dependence of tandem polybasic tracts with terrestrial status and with lungs, coincident with the ENaC activator aldosterone. Amplification of transcripts by RT‐PCR in ray‐finned Polypteriformes and previously in lobe‐finned lungfish suggest that transcripts for ENaC subunits with cleavage sites are readily detected at important sites of ion exchange (gills and kidney), but are difficult to detect in lungs. Analysis of ancestral reconstructions strongly suggests that the polybasic tracts appeared independently in the α and γ subunits of ENaC. Similar analyses of the PY motif, required for Nedd4‐2 dependent regulation, showed no coevolutionary pattern and that the PY motif first arose in an ancient ancestral ENaC subunit. Our data suggest that changes associated with adaptation to terrestrial life provided selective pressure for the development of ENaC activation by proteolytic cleavage.

Activation by cleavage of the epithelial Na+ channel α and γ subunits independently coevolved with the vertebrate terrestrial migration.

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel's α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the α and γ subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange were required for terrestrial survival.

Lymphatic Connexins and Pannexins in Health and Disease.

This review highlights current knowledge on the expression and function of connexins and pannexins, transmembrane channel proteins that play an important role in intercellular communication, in both the developing and mature lymphatic vasculature. A particular focus is given to the involvement of these proteins in functions of the healthy lymphatic system. We describe their influence on the maintenance of extracellular fluid homeostasis, immune cell trafficking to draining lymph nodes and dietary nutrient absorption by intestinal villi. Moreover, new insights into connexin mutations in primary and secondary lymphedema as well as on the implication of lymphatic connexins and pannexins in acquired cardiovascular diseases are discussed, allowing for a better understanding of the role of these proteins in pathologies linked to dysfunctions in the lymphatic system.

Nutritional and health factors affecting the bioavailability of calcium: a narrative review.

Calcium is responsible for the effectiveness of various processes, and its supply in the diet is necessary for the normal function of the human body. Apart from being an important component of the skeleton, calcium also helps maintain the structure of cell organelles and regulates intracellular and extracellular fluid homeostasis. This review presents the nutritional and health factors that affect the bioavailability of calcium. Physiological conditions and factors such as pregnancy, infancy, menopause, old age, hormones, growth factors associated with calcium metabolism, diseases limiting its absorption, and intestinal microbiota are distinguished among endogenous factors. Although the calcium supply in the body is genetically conditioned and specific to each person, its qualitative and quantitative composition can be modified by external factors. The exogenous factors include dietary modifications with particular nutrients and pharmacological treatment. Adequate calcium levels increase bone protection and prevent osteoporosis, a disease involving low mineral bone mass.

Structure and physiology of the lymphatic vasculature

The lymphatic vascular system is a highly organized network of structurally and functionally connected specialized lymphatic vessels of various sizes and lymph nodes that perform metabolic and transport functions. Lymph is a blood plasma filtrate that comprises antigen-presenting cells and lymphocytes. Via lymph, excess fluid and extravasated proteins are removed from the tissues. The lymphatic system supports an extracellular fluid homeostasis that is favorable for optimal tissue functioning by removing substances that result from metabolism or cell death, as well as optimizing immunity against bacteria, viruses and other antigens. Although the lymphatic vasculature is not formally considered part of the immune system, it is crucial for the traffic of antigens and immune cells. In addition, lymphatic endothelial cells can supply antigens and express factors that modulate immune responses. After an inflammatory stimulus, endothelial cells produce chemokines, which recruit immune cells to the lymph nodes. Unlike the circulatory system with a centralized pump, the movement of lymph through the network of lymphatic vessels is provided by forces that stimulate the initial formation of lymph in the tissues and the ability of the lymphatic vessels and nodes to rhythmically contract, providing increased pressure and lymph movement in the proximal direction. Since the metabolic rate in various organs and tissues varies significantly depending on the functional state of the tissue, the blood flow through the tissue and the amount of lymph formed also change significantly. The lymphatic vasculature has several circuits for regulating lymph flow. This review provides a comprehensive overview of the important results obtained over the past century and discusses the molecular and physiological control of the transport function of lymphatic vessels and nodes.

Structural Organization of Plasma Proteins as a Factor of Capillary Filtration in Pisces (Review)

Studies of capillary filtration (CF), which supports the isotonia of extracellular fluids in a vertebrate organism, are commonly considered within the “updated” Starling hypothesis developed on terrestrial vertebrates. This hypothesis explains the homeostasis of extracellular fluid in the body by the balance of the hydrostatic and oncotic pressures of plasma and interstitial fluid (the Starling forces) and the key role of plasma proteins in providing the capillary water transfer. The model is based on the intravascular localization of plasma proteins and the dominant contribution of albumin to its oncotic pressure (up to 80%). Due to a lack of antigravity adjustment in fish, the full recognition of Starling forces is considered incorrect. The review discusses a special “albumin-free” CF model for lower aquatic vertebrates. Like the classical one, this model proceeds from the key role of plasma proteins in the water transfer, but it also takes into account specific fish features such as a high concentration of total protein in interstitium, a high content of oligomeric proteins, and the absence of albumin (or its weak effect on water homeostasis). Oligomeric proteins play an important role in maintaining the isotonia of plasma and interstitial fluid due to their reorganization by associations/dissociations, which presumably contribute to the equalization of the fluid osmolality on both sides of the capillary wall and the maintenance of their isotonia in a wide range of environmental conditions.

Abstract 045: Attenuated Natriuretic Response to Saline Loading in Sheep With Hypertensive Kidney Disease Following Radiofrequency Catheter-Based Renal Denervation

In the present study, we examined the chronic effect of renal denervation (RDN) on the blood pressure (BP) and renal function in response to a slow-infused isotonic saline load. Normotensive (control) and hypertensive chronic kidney disease (CKD) sheep at 10 months of age underwent either a sham (control-intact; N=6, CKD-intact; N=7) or radiofrequency catheter-based RDN (control-RDN; N=7, CKD-RDN, N=7) procedure using the Symplicity catheter system. BP and renal function were measured during 3-h saline loading (0.9% NaCl, 0.13ml/kg/min) and 3-h recovery periods in animals at 2 and 11 months post-procedure. In this cohort of sheep, as previously reported, BP was reduced and GFR increased at 11 months in the CKD-RDN group. In response to saline loading, BP increased 3-5 mmHg in all groups. In response to saline loading sodium excretion increased in all groups. At 2 months post-procedure, the control-intact group excreted 66±7% of the sodium load over the 6-h period, whereas the response was exaggerated in the CKD-intact group (92±9%; P<0.001 vs. control-intact) but blunted in the RDN groups (control-RDN 32±5%; CKD-RDN 63±5%; both P<0.01 vs. intact). However, by 11 months post-procedure, the % excretion of the sodium load was similar in the intact (53±4%) and RDN (65±5%) control groups, but remained attenuated in the CKD-RDN group (33±6% P<0.001 vs. CKD-intact, 63±14%). Together these data indicate that (1) the normal suppression of RSNA activity during saline loading contributes to the rapid elimination of excess sodium and water, (2) following RDN the excretion of a saline load is attenuated and (3) this effect was maintained for 11 months in the CKD-RDN group indicating nerve regrowth is not complete. In conclusion, RDN in patients with hypertensive CKD may slow the return of extracellular fluid homeostasis in response to physiological challenges such as volume expansion.

Role of Aldosterone in Renal Fibrosis.

Aldosterone is a mineralocorticoid hormone, as its main renal effect has been considered as electrolyte and water homeostasis in the distal tubule, thus maintaining blood pressure and extracellular fluid homeostasis through the activation of mineralocorticoid receptor (MR) in epithelial cells. However, over the past decade, numerous studies have documented the significant role of aldosterone in the progression of chronic kidney disease (CKD) which has become a subject of interest. It is being studied that aldosterone can affect cardiovascular and renal system, thereby contributing to tissue inflammation, injury, glomerulosclerosis, and interstitial fibrosis. Aldosterone acts on renal vessels, renal cells (glomerular mesangial cells, podocytes, vascular smooth muscle cells, tubular epithelial cells, and interstitial fibroblasts), and infiltrating inflammatory cells, inducing reactive oxygen species (ROS) production, upregulated epithelial growth factor receptor (EGFR), and type 1 angiotensin (AT1) receptor expressions, and activating nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and EGFR to further promote cell proliferation, apoptosis, and proliferation. Phenotypic transformation of epithelial cells stimulates the expression of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), osteopontin (OPN), and plasminogen activator inhibitor-1 (PAI-1), eventually leading to renal fibrosis. MR antagonisms are related to inhibition of aldosterone-mediated pro-inflammatory and pro-fibrotic effect. In this review, we will summarize the important role of aldosterone in the pathogenesis of renal injury and fibrosis, emphasizing on its multiple underlying mechanisms and advances in aldosterone research along with the potential therapeutics for targeting MR in a renal fibrosis.

Lymphatic Vessel Network Structure and Physiology.

The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease. © 2019 American Physiological Society. Compr Physiol 9:207-299, 2019.

Slippery When Wet: Airway Surface Liquid Homeostasis and Mucus Hydration.

The ability to regulate cell volume is crucial for normal physiology; equally the regulation of extracellular fluid homeostasis is of great importance. Alteration of normal extracellular fluid homeostasis contributes to the development of several diseases including cystic fibrosis. With regard to the airway surface liquid (ASL), which lies apically on top of airway epithelia, ion content, pH, mucin and protein abundance must be tightly regulated. Furthermore, airway epithelia must be able to switch from an absorptive to a secretory state as required. A heterogeneous population of airway epithelial cells regulate ASL solute and solvent composition, and directly secrete large mucin molecules, antimicrobials, proteases and soluble mediators into the airway lumen. This review focuses on how epithelial ion transport influences ASL hydration and ASL pH, with a specific focus on the roles of anion and cation channels and exchangers. The role of ions and pH in mucin expansion is also addressed. With regard to fluid volume regulation, we discuss the roles of nucleotides, adenosine and the short palate lung and nasal epithelial clone 1 (SPLUNC1) as soluble ASL mediators. Together, these mechanisms directly influence ciliary beating and in turn mucociliary clearance to maintain sterility and to detoxify the airways. Whilst all of these components are regulated in normal airways, defective ion transport and/or mucin secretion proves detrimental to lung homeostasis as such we address how defective ion and fluid transport, and a loss of homeostatic mechanisms, contributes to the development of pathophysiologies associated with cystic fibrosis.

Vasopressin lowers renal epoxyeicosatrienoic acid levels by activating soluble epoxide hydrolase.

Activation of the thick ascending limb (TAL) Na+-K+-2Cl- cotransporter (NKCC2) by the antidiuretic hormone arginine vasopressin (AVP) is an essential mechanism of renal urine concentration and contributes to extracellular fluid and electrolyte homeostasis. AVP effects in the kidney are modulated by locally and/or by systemically produced epoxyeicosatrienoic acid derivates (EET). The relation between AVP and EET metabolism has not been determined. Here, we show that chronic treatment of AVP-deficient Brattleboro rats with the AVP V2 receptor analog desmopressin (dDAVP; 5 ng/h, 3 days) significantly lowered renal EET levels (-56 ± 3% for 5,6-EET, -50 ± 3.4% for 11,12-EET, and -60 ± 3.7% for 14,15-EET). The abundance of the principal EET-degrading enzyme soluble epoxide hydrolase (sEH) was increased at the mRNA (+160 ± 37%) and protein levels (+120 ± 26%). Immunohistochemistry revealed dDAVP-mediated induction of sEH in connecting tubules and cortical and medullary collecting ducts, suggesting a role of these segments in the regulation of local interstitial EET signals. Incubation of murine kidney cell suspensions with 1 μM 14,15-EET for 30 min reduced phosphorylation of NKCC2 at the AVP-sensitive threonine residues T96 and T101 (-66 ± 5%; P < 0.05), while 14,15-DHET had no effect. Concomitantly, isolated perfused cortical thick ascending limb pretreated with 14,15-EET showed a 30% lower transport current under high and a 70% lower transport current under low symmetric chloride concentrations. In summary, we have shown that activation of AVP signaling stimulates renal sEH biosynthesis and enzyme activity. The resulting reduction of EET tissue levels may be instrumental for increased NKCC2 transport activity during AVP-induced antidiuresis.

The plasticity of extracellular fluid homeostasis in insects.

In chemistry, the ratio of all dissolved solutes to the solution's volume yields the osmotic concentration. The present Review uses this chemical perspective to examine how insects deal with challenges to extracellular fluid (ECF) volume, solute content and osmotic concentration (pressure). Solute/volume plots of the ECF (hemolymph) reveal that insects tolerate large changes in all three of these ECF variables. Challenges beyond those tolerances may be 'corrected' or 'compensated'. While a correction simply reverses the challenge, compensation accommodates the challenge with changes in the other two variables. Most insects osmoregulate by keeping ECF volume and osmotic concentration within a wide range of tolerance. Other insects osmoconform, allowing the ECF osmotic concentration to match the ambient osmotic concentration. Aphids are unique in handling solute and volume loads largely outside the ECF, in the lumen of the gut. This strategy may be related to the apparent absence of Malpighian tubules in aphids. Other insects can suspend ECF homeostasis altogether in order to survive extreme temperatures. Thus, ECF homeostasis in insects is highly dynamic and plastic, which may partly explain why insects remain the most successful class of animals in terms of both species number and biomass.

Activation of a Novel Adaptive Mechanism Limits Renal Salt Wasting During Thiazide Inhibition of the Sodium Chloride Cotransporter (NCC)

NCC reabsorbs approximately 10% of filtered NaCl, an amount vital for maintaining extracellular electrolyte and fluid homeostasis. Thiazide inhibition of NCC is used clinically to reduce extracellular fluid volume in treatment of hypertension, but the drugs efficacy often wanes along with its natriuretic properties suggesting activation of another NaCl reabsorptive pathway. Here, we describe an adaptive process in mice given thiazides. Transcriptional profiling, together with protein abundance analysis, reveals an intercalated cell pathway synergizes with a α‐ketoglutarate (αKG) paracrine signaling system to augment sodium chloride reabsorption in distal nephron. Coordinate transcriptional activation of a multi‐gene transport system in pendrin positive intercalated cells (PPIC), involving solute carriers (Slc26a;Slc4a8; Slc4a9), carbonic anhydrase 2 &amp; 15, and V‐type H+‐ATPase, collectively form an electroneutral NaCl reabsorption pathway. In the proximal tubule, transcript for glutamine (Slc6a19, Slc38a2, Slc38a3), glutamate (Slc7a13) and α‐KG carriers (Slc22a13, Slc13a2, Slc13a3, Slc22a6) increase, along with the enzymes (Gls &amp; Glud1) responsible for αKG synthesis from these amino acids. Consequently, aKG in tubular fluid is elevated, as is the abundance of its GPCR (Oxgr1), which is expressed on the apical surface of PPIC, allowing paracrine delivery of αKG to stimulate the transport pathway. Identification of the integrated compensatory NaCl reabsorption mechanism provides new molecular targets for diuretics and highlights a potential cause of thiazide resistance.

Cellular and molecular cues of glucose sensing in the rat olfactory bulb.

In the brain, glucose homeostasis of extracellular fluid is crucial to the point that systems specifically dedicated to glucose sensing are found in areas involved in energy regulation and feeding behavior. Olfaction is a major sensory modality regulating food consumption. Nutritional status in turn modulates olfactory detection. Recently it has been proposed that some olfactory bulb (OB) neurons respond to glucose similarly to hypothalamic neurons. However, the precise molecular cues governing glucose sensing in the OB are largely unknown. To decrypt these molecular mechanisms, we first used immunostaining to demonstrate a strong expression of two neuronal markers of glucose-sensitivity, insulin-dependent glucose transporter type 4 (GLUT4), and sodium glucose co-transporter type 1 (SGLT1) in specific OB layers. We showed that expression and mapping of GLUT4 but not SGLT1 were feeding state-dependent. In order to investigate the impact of metabolic status on the delivery of blood-borne glucose to the OB, we measured extracellular fluid glucose concentration using glucose biosensors simultaneously in the OB and cortex of anesthetized rats. We showed that glucose concentration in the OB is higher than in the cortex, that metabolic steady-state glucose concentration is independent of feeding state in the two brain areas, and that acute changes in glycemic conditions affect bulbar glucose concentration alone. These data provide new evidence of a direct relationship between the OB and peripheral metabolism, and emphasize the importance of glucose for the OB network, providing strong arguments toward establishing the OB as a glucose-sensing organ.

Impaired ability to modulate glomerular filtration rate in aged female sheep following fetal uninephrectomy.

Fetal uninephrectomy (uni‐x) results in hypertension at a later age in female than male sheep. We hypothesized that dysregulation of tubular sodium handling contributes to the reduced ability to regulate extracellular fluid (ECF) homeostasis in older females born with a congenital nephron deficit. Following renal excretory balance studies, the response to inhibition of the Na+K+2Cl− cotransporter with furosemide (0.5 mg/kg bolus + 1 mg/kg per hour, i.v) or vehicle treatment was examined in conscious 5‐year‐old female uni‐x (n = 7) and sham (n = 7) sheep. Balance studies in meal‐fed sheep demonstrated that while average 24 h sodium excretion over 6 days was not different between the groups, the daily variation in sodium excretion was significantly greater in uni‐x compared to sham sheep (31 ± 4% vs. 12 ± 2%; P < 0.001). Basal plasma renin activity (PRA) and renal cortical cyclooxygenase‐2 (COX‐2) gene expression were lower in uni‐x sheep (both, P < 0.01). The increases in glomerular filtration rate (GFR) and renal blood flow observed in sham sheep in response to furosemide were significantly attenuated in uni‐x sheep (both PGROUP×TREAT < 0.05). However, fractional sodium excretion increased by a greater extent in the uni‐x (4.4 ± 1.0%) as compared to the sham sheep (2.0 ± 0.4%; PGROUP×TIME < 0.05) in response to furosemide. In conclusion, fetal uni‐x was associated with altered renal sodium handling and hypertension in aged females. The impaired ability to modulate PRA and GFR in the adults with a congenital nephron deficit may reduce the capacity of the kidney to respond to gains or losses in ECF to maintain a stable internal environment.

Blunted sodium excretion in response to a saline load in 5 year old female sheep following fetal uninephrectomy.

Previously, we have shown that fetal uninephrectomy (uni-x) causes hypertension in female sheep by 2 years of age. Whilst the hypertension was not exacerbated by 5 years of age, these uni-x sheep had greater reductions in renal blood flow (RBF). To further explore these early indications of a decline in renal function, we investigated the renal response to a saline load (25 ml/kg/40 min) in 5-year old female uni-x and sham sheep. Basal mean arterial pressure was ∼15 mmHg greater (PGroup<0.001), and sodium excretion (∼50%), glomerular filtration rate (∼30%, GFR) and RBF (∼40%) were all significantly lower (PGroup<0.01) in uni-x compared to sham animals. In response to saline loading, sodium excretion increased significantly in both groups (PTime<0.001), however this response was blunted in uni-x sheep (PGroupxTime<0.01). This was accompanied with an attenuated increase in GFR and fractional sodium excretion (both PGroupxTime<0.05), and reduced activation of the renin-angiotensin system (both P<0.05), as compared to the sham group. The reduction in sodium excretion was associated with up-regulations in the renal gene expression of NHE3 and Na+/K+ ATPase α and β subunits in the kidney cortex of the uni-x compared to the sham animals (P<0.05). Notably, neither group completely excreted the saline load within the recovery period, but the uni-x retained a higher percentage of the total volume (uni-x: 48±7%; sham: 22±9%, P<0.05). In conclusion, a reduced ability to efficiently regulate extracellular fluid homeostasis is evident in female sheep at 5 years of age, which was exacerbated in animals born with a congenital nephron deficit. Whilst there was no overt exacerbation of hypertension and renal insufficiency with age in the uni-x sheep, these animals may be more vulnerable to secondary renal insults.

Immunofluorescent localization of the Rab-GAP protein TBC1D4 (AS160) in mouse kidney

TBC1D4 (or AS160) was identified as a Rab-GTPase activating protein (Rab-GAP) that controls insulin-dependent trafficking of the glucose transporter GLUT4 in skeletal muscle cells and in adipocytes. Recent in vitro cell culture studies suggest that TBC1D4 may also regulate the intracellular trafficking of kidney proteins such as the vasopressin-dependent water channel AQP2, the aldosterone-regulated epithelial sodium channel ENaC, and the Na(+)-K(+)-ATPase. To study the possible role of TBC1D4 in the kidney in vivo, we raised a rabbit polyclonal antibody against TBC1D4 to be used for immunoblotting and immunohistochemical studies. In immunoblots on mouse kidney homogenates, the antibody recognizes specific bands at the expected size of 160 kDa and at lower molecular weights, which are absent in kidneys of TBC1D4 deficient mice. Using a variety of nephron-segment-specific marker proteins, immunohistochemistry reveals TBC1D4 in the cytoplasm of the parietal epithelial cells of Bowman's capsule, the thin and thick limbs of Henle's loop, the distal convoluted tubule, the connecting tubule, and the collecting duct. In the latter, both principal as well as intercalated cells are TBC1D4-positive. Thus, with the exception of the proximal tubule, TBC1D4 is highly expressed along the nephron and the collecting duct, where it may interfere with the intracellular trafficking of many renal transport proteins including AQP2, ENaC and Na(+)-K(+)-ATPase. Hence, TBC1D4 may play an important role for the control of renal ion and water handling and hence for the control of extracellular fluid homeostasis.

Angiotensin II, Aldosterone, and Anti-Inflammatory Lymphocytes: Interplay and Therapeutic Opportunities

Inflammation is recognized as an important factor in the pathophysiology of hypertension, with the renin-angiotensin-aldosterone system (RAAS) playing a key role in the disease. Initially described because of its contribution to extracellular fluid and electrolyte homeostasis, the RAAS has been implicated in endothelial dysfunction, vascular remodeling, oxidative stress, proinflammatory cytokine production, and adhesion molecule synthesis by the vascular wall. Both angiotensin II and aldosterone are involved in these systemic effects, activating innate and adaptive immune responses. This paper highlights some aspects connecting RAAS to the hypertensive phenotype, based on experimental and clinical studies, with emphasis on new findings regarding the contribution of an increasingly studied population of T lymphocytes: the T-regulatory lymphocytes. These cells can suppress inflammation and may exert beneficial vascular effects in animal models of hypertension.

Renal programming: cause for concern?

Development of the kidney can be altered in utero in response to a suboptimal environment. The intrarenal factors that have been most well characterized as being sensitive to programming events are kidney mass/nephron endowment, the renin-angiotensin system, tubular sodium handling, and the renal sympathetic nerves. Newborns that have been subjected to an adverse intrauterine environment may thus begin life at a distinct disadvantage, in terms of renal function, at a time when the kidney must take over the primary role for extracellular fluid homeostasis from the placenta. A poor beginning, causing renal programming, has been linked to increased risk of hypertension and renal disease in adulthood. However, although a cause for concern, increasingly, evidence demonstrates that renal programming is not a fait accompli in terms of future cardiovascular and renal disease. A greater understanding of postnatal renal maturation and the impact of secondary factors (genes, sex, diet, stress, and disease) on this process is required to predict which babies are at risk of increased cardiovascular and renal disease as adults and to be able to devise preventative measures.