Renal Water Reabsorption Research Articles

The Paradise Renal Denervation System: An FDA-approved catheter-based treatment option for resistant hypertension

Resistant hypertension is defined as office blood pressure >140/90 mm Hg with a mean 24-hour ambulatory blood pressure of >130/80 mm Hg in patients who are compliant with 3 or more antihypertensive medications. Those who persistently fail pharmaceutical therapy may benefit from interventional treatment, such as renal denervation. Sympathetic nervous activity in the kidney is a known contributor to increased blood pressure because it results in efferent and afferent arteriole vasoconstriction, reduced renal blood flow, increased sodium and water reabsorption, and the release of renin. The Recor Paradise Renal Denervation System is designed to target renal sympathetic nerves via ultrasound ablation. The RADIANCE trials have demonstrated that patients who underwent renal denervation had a significant decrease in systolic blood pressure as compared with those who underwent a sham procedure. Furthermore, the device was found to have a favorable safety profile, with minimal major adverse events. The Food and Drug Administration granted approval to Recor, and the Paradise system is expected to serve as an adjunctive therapy for patients with true-resistant hypertension.

Update on Tolvaptan for the Treatment of Refractory Ascites in Liver Cirrhosis

Ascites is the most prevalent complication of decompensated cirrhosis, and approximately 5%-10% of cirrhotic ascites will develop into refractory ascites (RA). With complicated pathogenesis, obscure treatment strategies and poor prognosis, it is still a challenge for physicians to manage RA properly. Tolvaptan (TLV) is a new type of non-peptide selective arginine vasopressin V2 receptor antagonist targeting at suppressing renal water reabsorption, promoting free water excretion and raising blood sodium levels, which provides a new option for the treatment of RA in liver cirrhosis. In this review, we summarized the mechanisms of TLV's effect and described its efficacy, safety and predictive factors of response in treating RA, intending to provide a supplement for clinical application of tolvaptan in the management of RA.

Increased urinary creatinine during hibernation and day roosting in the Eastern bent-winged bat (Miniopterus fuliginosus) in Korea

Torpor and arousal cycles, both daily and seasonal (e.g. hibernation), are crucial for small mammals, including bats, to maintain the energy and water balance. The alternation between torpor and arousal leads to metabolic changes, leaving traceable evidence of metabolic wastes in urine. In this study we investigated urinary creatinine and acetoacetate (a ketone body) in the Eastern bent-wing bat (Miniopterus fuliginosus) in Mungyeong, South Korea. We found an increase in urinary creatinine during torpor in summer, indicating changes in renal water reabsorption rates during the active season. Although we could not confirm ketonuria in hibernating bats due to a methodological limitation caused by the small amount of urine, we verified an increase in urinary creatinine concentration during hibernation. This finding suggests that managing water stress resulting from evaporative water loss is one of key reasons for arousal during hibernation in Eastern bent-wing bats.

Characteristics of Nutrition and Metabolism in Dogs and Cats.

Domestic dogs and cats have evolved differentially in some aspects of nutrition, metabolism, chemical sensing, and feeding behavior. The dogs have adapted to omnivorous diets containing taurine-abundant meat and starch-rich plant ingredients. By contrast, domestic cats must consume animal-sourced foods for survival, growth, and development. Both dogs and cats synthesize vitamin Cand many amino acids (AAs, such as alanine, asparagine, aspartate, glutamate, glutamine, glycine, proline, and serine), but have a limited ability to form de novo arginine and vitamin D3. Compared with dogs, cats have greater endogenous nitrogen losses and higher dietary requirements for AAs (particularly arginine, taurine, and tyrosine), B-complex vitamins (niacin, thiamin, folate, and biotin), and choline; exhibit greater rates of gluconeogenesis; are less sensitive to AA imbalances and antagonism; are more capable of concentrating urine through renal reabsorption of water; and cannot tolerate high levels of dietary starch due to limited pancreatic α-amylase activity. In addition, dogs can form sufficient taurine from cysteine (formost breeds); arachidonic acid from linoleic acid; eicosapentaenoic acid and docosahexaenoic acid from α-linolenic acid; all-trans-retinol from β-carotene; and niacin from tryptophan. These synthetic pathways, however, are either absent or limited in all cats due to (a)no or low activities of key enzymes (including pyrroline-5-carboxylate synthase, cysteine dioxygenase, ∆6-desaturase, β-carotene dioxygenase, and quinolinate phosphoribosyltransferase)and (b) diversion of intermediates to other metabolic pathways. Dogs can thrive on one large meal daily, select high-fat over low-fat diets, and consume sweet substances. By contrast, cats eat more frequently during light and dark periods, select high-protein over low-protein diets, refuse dry food, enjoy a consistent diet, and cannot taste sweetness. This knowledge guides the feeding and care of dogs and cats, as well as the manufacturing of their foods. As abundant sources of essential nutrients, animal-derived foodstuffs play important roles in optimizing the growth, development, and health of the companion animals.

Activation of TGR5 Increases Urine Concentration by Inducing AQP2 and AQP3 Expression in Renal Medullary Collecting Ducts

Introduction: G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular signaling pathways after interacting with bile acids. TGR5 plays an important role in multiple physiological processes and is considered to be a potential target for the treatment of various metabolic diseases, including type 2 diabetes. Evidence has emerged that genetic deletion of TGR5 results in an increase in basal urine output, suggesting that it may play a critical role in renal water and salt reabsorption. The present study aims to elucidate the effect and mechanism of TGR5 activation on urine concentration. Methods: Mice were treated with TGR5 agonists (LCA and INT-777) for 3 days. The 24-h urine of mice was collected and analyzed for urine biochemical parameters. The mRNA expressions were detected by real-time PCR, and the protein expressions were detected by western blot. Immunohistochemistry and immunofluorescence were performed to examine the cellular location of proteins. The cultured primary medullary collecting duct cells were pretreated with H89 (a PKA inhibitor) for 1 h, followed by 12-h treatment of LCA and INT-777. Luciferase reporter assays were used to detect the effect of CREB on the gene transcription of AQPs. Gel electrophoretic mobility shift assays were used to analyze DNA–protein interactions. Results: Treatment of mice with the TGR5 agonist LCA and INT-777 markedly reduced urine output and increased urine osmolality, accompanied by a marked increase in AQP2 and AQP3 protein expression and membrane translocation. In cultured primary medullary collecting duct cells, LCA and INT-777 dose-dependently upregulated AQP2 and AQP3 expression in a cAMP/PKA-dependent manner. Mechanistically, both AQP2 and AQP3 gene promoter contains a putative CREB-binding site, which can be bound and activated by CREB as assessed by both gene promoter-driven luciferase and gel shift assays. Conclusion: Collectively, our findings demonstrate that activation of TGR5 can promote urine concentration by upregulation of AQP2 and AQP3 expression in renal collecting ducts. TGR5 may represent an attractive target for the treatment of patients with urine concentration defect.

Following the cellular itinerary of renal aquaporin-2 shuttling with 4.5x expansion microscopy.

The shuttling of renal collecting duct aquaporin-2 (AQP2) between intracellular vesicles and the apical plasma membrane is paramount for regulation of renal water reabsorption. The binding of the circulating antidiuretic hormone arginine vasopressin (AVP) to the basolateral AVP receptor increases intracellular cAMP, which ultimately leads to AQP2 plasma membrane accumulation via a dual effect on AQP2 vesicle fusion with the apical plasma membrane and reduced AQP2 endocytosis. This AQP2 plasma membrane accumulation increases water reabsorption and consequently urine concentration. Conventional fluorescent microscopy provides a lateral resolution of ∼250 nm, which is insufficient to resolve the AQP2-containing endosomes/vesicles. Therefore, detailed information regarding the AQP2 vesicular population is still lacking. Newly established 4.5x Expansion Microscopy (ExM) can increase resolution to 60-70 nm. Using 4.5x ExM, we detected AQP2 vesicles/endosomes as small as 79 nm considering an average expansion factor of 4.3 for endosomes. Using different markers of the endosomal system provided detailed information of the cellular AQP2 itinerary upon changes in endogenous cAMP levels. Before cAMP elevation, AQP2 colocalized with early and recycling, but not late endosomes. Forskolin-induced cAMP increase was characterized by AQP2 insertion into the plasma membrane and AQP2 withdrawal from large perinuclear endosomes as well as some localization to lysosomal compartments. Forskolin washout promoted AQP2 endocytosis where AQP2 localized to not only early and recycling endosomes but also late endosomes and lysosomes indicating increased AQP2 degradation. Thus, our results show that 4.5 ExM is an attractive approach to obtain detailed information regarding AQP2 shuttling.NEW & NOTEWORTHY Renal aquaporin-2 (AQP2) imaged by expansion microscopy provides unprecedented 3-D information regarding the AQP2 itinerary in response to changes in cellular cAMP.

Bile acid receptors and renal regulation of water homeostasis.

The kidney is the key organ responsible for maintaining the body's water and electrolyte homeostasis. About 99% of the primary urine filtered from the Bowman's capsule is reabsorbed along various renal tubules every day, with only 1-2L of urine excreted. Aquaporins (AQPs) play a vital role in water reabsorption in the kidney. Currently, a variety of molecules are found to be involved in the process of urine concentration by regulating the expression or activity of AQPs, such as antidiuretic hormone, renin-angiotensin-aldosterone system (RAAS), prostaglandin, and several nuclear receptors. As the main bile acid receptors, farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor 1 (TGR5) play important roles in bile acid, glucose, lipid, and energy metabolism. In the kidney, FXR and TGR5 exhibit broad expression across all segments of renal tubules, and their activation holds significant therapeutic potential for numerous acute and chronic kidney diseases through alleviating renal lipid accumulation, inflammation, oxidative stress, and fibrosis. Emerging evidence has demonstrated that the genetic deletion of FXR or TGR5 exhibits increased basal urine output, suggesting that bile acid receptors play a critical role in urine concentration. Here, we briefly summarize the function of bile acid receptors in renal water reabsorption and urine concentration.

Nonatherosclerotic Renovascular Hypertension.

Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the renin-angiotensin-aldosterone system. Often, this occurs due to abnormally small, narrowed, or blocked blood vessels supplying one or both kidneys (ie: renal artery occlusive disease) and is correctable. Juxtaglomerular cells release renin in response to decreased pressure, which in turn catalyzes the cleavage of circulating angiotensinogen synthesized by the liver to the decapeptide angiotensin I. Angiotensin-converting enzyme then cleaves angiotensin I to form the octapeptide angiotensin II, a potent vasopressor and the primary effector of renin-induced hypertension. The effects of angiotensin II are mediated by signaling downstream of its receptors. Angiotensin receptor type 1 is a G-protein-coupled receptor that activates vasoconstrictor and mitogenic signaling pathways resulting in peripheral arteriolar vasoconstriction and increased renal tubular reabsorption of sodium and water which promotes intravascular volume expansion. Angiotensin II stimulates the adrenal cortical release of aldosterone, which promotes renal tubular sodium reabsorption, resulting in volume expansion. Angiotensin II acts on glial cells and regions of the brain responsible for blood pressure regulation increasing renal sympathetic activation. Angiotensin II simulates the release of vasopressin from the pituitary which stimulates thirst and water reabsorption from the kidney to expand the intravascular volume and cause peripheral vasoconstriction (increased sympathetic tone). All of these mechanisms coalesce to increase arterial pressure by way of arteriolar constriction, enhanced cardiac output, and the retention of sodium and water.

AT1 receptor role in the hypothalamic and renal function interaction

Angiotensin II (ANG II) is involved in renal sodium homeostasis under normal and pathological conditions in close relation with the sympathetic nervous system. Vasopressin, a hormone that modulates renal sodium and water reabsorption, is synthesized and released in the supraoptic and paraventricular nucleus under the influence of ANG II. We hypothesized that brain ANG II (AT1) receptors regulate renal sodium and water reabsorption and excretion through the sympathetic nervous system. In this study, male Wistar rats with renal denervation/sham were fed a hypersodic (4%) or normal (0.4%) diet and evaluated during 5 days in metabolic cages. On day 5, they were injected in the lateral ventricle with an AT1 receptor antagonist, losartan, and sacrificed 12 h later; blood samples and brains were obtained for evaluation. The urine was collected daily. The neuronal activation was analyzed in the nucleus of the supraoptic, paraventricular, subfornical, and organum vasculosum of the lamina terminalis. Activation of vasopressin neurons was evaluated in the supraoptic nucleus. Depending on renal nerve integrity, the hypersodic diet or losartan administration differentially affected neuronal activation. In sham animals, losartan prevented the stimulatory effects induced by the hypersodic diet in water intake and the neuronal activation in vasopressin-positive neurons. Renal denervation modified the effect of the hypersodic diet on water intake, urinary volume, and creatinine excretion, and losartan administration was able to prevent these alterations. Food intake was similar in all groups. Our results suggest that brain AT1 receptors regulate renal sodium and water reabsorption through the sympathetic nervous system in close interaction with vasopressin.

Antioxidant, antihyperglycemic, and antihyperlipidemic properties of Chimonanthus salicifolius S. Y. Hu leaves in experimental animals: modulation of thioredoxin and glutathione systems, renal water reabsorption, and gut microbiota.

Excessive calorie intake and physical inactivity have dramatically increased nutrient overload-associated disease, becoming a global public health issue. Chimonanthus salicifolius S. Y. Hu (CHI) is a homology plant of food and medicine in China and shows several health benefits. This work investigated the antioxidant activity, the alleviating effects, and the mechanism of action on diabetes and hyperlipidemia of CHI leaves. Results showed that CHI leaves infusion displayed in vitro antioxidant activity measured by ABTS and ferric reducing antioxidant power methods. In wild-type Kunming mice, CHI leaves infusion consumption activated the hepatic antioxidant enzymes, including glutathione reductase, glutathione S-transferase, glutathione peroxidase and thioredoxin reductase as well as thioredoxin reductase 1. In alloxan-induced type 1 diabetic mice, CHI leaves infusion ameliorated diabetic symptoms, including polyuria, polydipsia, polyphagia and hyperglycemia, in a dose-dependent and time-course manners. The mechanism involved CHI leaves up-regulating renal water reabsorption associated protein - urine transporter A1-and promoting the trafficking of urine transporter A1 and aquaporin 2 to the apical plasma membrane. Despite this, in high-fat diet-induced hyperlipidemic golden hamsters, CHI leaves powder did not significantly effect on hyperlipidemia and body weight gain. This might be attributed to CHI leaves powder increasing the calorie intake. Interestingly, we found that CHI leaves extract containing a lower dose of total flavonoid than CHI leaves powder pronouncedly reduced the levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum in golden hamsters fed a high-fat diet. Furthermore, CHI leaves extract elevated the diversity of gut microbiota and the abundance of Bifidobacterium and Ruminococcaceae_UCG-014. It also decreased the abundance of Lactobacillus at the genus level in golden hamsters fed a high-fat diet. Overall, CHI leaves benefit oxidative stress prevention and metabolic syndrome amelioration in vivo.

Role of the Renal Lymphatic System in Heart Failure.

The lymphatic system plays a major but overlooked role in maintaining fluid homeostasis. Given the unique fluid homeostasis functions of the kidneys, dysregulation of the renal lymphatic system underlies the development of self-propagating congestive pathomechanisms. In this review, we outline the roles of the renal lymphatic system in heart failure (HF). Studies have uncovered several pathomechanisms involving the renal lymphatic system in congestive states, such as impaired interstitial draining by the renal lymphatic system, impaired structure and valves of renal lymphatics, lymphatic-induced increase in renal reabsorption of water and sodium, and development of albuminuria with proteinuria-induced renal lymphangiogenesis. These self-propagating mechanisms result in "renal tamponade" with manifestations of cardiorenal syndrome and inappropriate renal response to diuretics. Dysregulation of the renal lymphatic system is integral to the development and progression of congestion in HF. Targeting renal lymphatics may provide a novel pathway to treat intractable congestion.

Serum sodium as a diabetes risk factor?

Electrolytes play a key role in controlling fluid status, muscle contraction, neurological function, coagulation, and acid base status, as well as multiple enzymatic reactions. Diabetes is associated with multiple significant electrolyte disorders, predominantly affecting serum sodium (Na), potassium, and magnesium.1 In healthy individuals, serum Na levels range between 135–146 mmol/L. Hyponatremia is defined as a serum Na < 135 mmol/L, typically accompanied by a low serum osmolality (<275 mosm/L). It is the most frequently seen electrolyte disorder, present in about 5% of adults and 35% of hospitalized patients.2, 3 In a New York health system analysis of 10 385 patients hospitalized with COVID-19 in 2020, hyponatremia was present in 37.5% of patients.4 Low serum Na may activate the renin-angiotensin-aldosterone system, may cause increased sympathetic nervous system tone, and may be associated with oxidative stress. Insulin, either administered therapeutically or in the setting of hyperinsulinemia from insulin resistance, increases renal tubular water reabsorption via a presumed vasopressin effect and can result in hyponatremia. Chronic kidney disease and diuretic use in hypertension further increase the risk of hyponatremia as well as other electrolyte imbalances such as hypokalemia and hypomagnesemia.7 Serum Na simply may represent the state of hydration. Might some of these mechanisms contribute to effects of even small deviations in serum Na from normal? Should we look more carefully at Na as a biomarker of outcome? Further analysis of large clinical data sets may give answers to these questions.

Role of FXR in Renal Physiology and Kidney Diseases.

Farnesoid X receptor, also known as the bile acid receptor, belongs to the nuclear receptor (NR) superfamily of ligand-regulated transcription factors, which performs its functions by regulating the transcription of target genes. FXR is highly expressed in the liver, small intestine, kidney and adrenal gland, maintaining homeostasis of bile acid, glucose and lipids by regulating a diverse array of target genes. It also participates in several pathophysiological processes, such as inflammation, immune responses and fibrosis. The kidney is a key organ that manages water and solute homeostasis for the whole body, and kidney injury or dysfunction is associated with high morbidity and mortality. In the kidney, FXR plays an important role in renal water reabsorption and is thought to perform protective functions in acute kidney disease and chronic kidney disease, especially diabetic kidney disease. In this review, we summarize the recent advances in the understanding of the physiological and pathophysiological function of FXR in the kidney.

Kinase Activity Is Not Required for G Protein-Coupled Receptor Kinase 4 Restraining mTOR Signaling during Cilia and Kidney Development.

G protein-coupled receptor kinase 4 (GRK4) regulates renal sodium and water reabsorption. Although GRK4 variants with elevated kinase activity have been associated with salt-sensitive or essential hypertension, this association has been inconsistent among different study populations. In addition, studies elucidating how GRK4 may modulate cellular signaling are sparse. In an analysis of how GRK4 affects the developing kidney, the authors found that GRK4 modulates mammalian target of rapamycin (mTOR) signaling. Loss of GRK4 in embryonic zebrafish causes kidney dysfunction and glomerular cysts. Moreover, GRK4 depletion in zebrafish and cellular mammalian models results in elongated cilia. Rescue experiments suggest that hypertension in carriers of GRK4 variants may not be explained solely by kinase hyperactivity; instead, elevated mTOR signaling may be the underlying cause. G protein-coupled receptor kinase 4 (GRK4) is considered a central regulator of blood pressure through phosphorylation of renal dopaminergic receptors and subsequent modulation of sodium excretion. Several nonsynonymous genetic variants of GRK4 have been only partially linked to hypertension, although these variants demonstrate elevated kinase activity. However, some evidence suggests that function of GRK4 variants may involve more than regulation of dopaminergic receptors alone. Little is known about the effects of GRK4 on cellular signaling, and it is also unclear whether or how altered GRK4 function might affect kidney development. To better understand the effect of GRK4 variants on the functionality of GRK4 and GRK4's actions in cellular signaling during kidney development, we studied zebrafish, human cells, and a murine kidney spheroid model. Zebrafish depleted of Grk4 develop impaired glomerular filtration, generalized edema, glomerular cysts, pronephric dilatation, and expansion of kidney cilia. In human fibroblasts and in a kidney spheroid model, GRK4 knockdown produced elongated primary cilia. Reconstitution with human wild-type GRK4 partially rescues these phenotypes. We found that kinase activity is dispensable because kinase-dead GRK4 (altered GRK4 that cannot result in phosphorylation of the targeted protein) prevented cyst formation and restored normal ciliogenesis in all tested models. Hypertension-associated genetic variants of GRK4 fail to rescue any of the observed phenotypes, suggesting a receptor-independent mechanism. Instead, we discovered unrestrained mammalian target of rapamycin signaling as an underlying cause. These findings identify GRK4 as novel regulator of cilia and of kidney development independent of GRK4's kinase function and provide evidence that the GRK4 variants believed to act as hyperactive kinases are dysfunctional for normal ciliogenesis.

Forensic Diagnosis of Freshwater or Saltwater Drowning Using the Marker Aquaporin 5: An Immunohistochemical Study.

Background and Objectives: Aquaporins are a family of water channel proteins. In this study, the renal and intrapulmonary expression of aquaporin-5 (AQP5) was examined in forensic autopsy cases to evaluate it as a drowning marker and to differentiate between freshwater drowning and saltwater drowning. Materials and Methods: Cases were classified into three groups: freshwater drowning (FWD), saltwater drowning (SWD), and controls (CTR). Samples were obtained from forensic autopsies at less than 72 h postmortem (15 FWD cases, 15 SWD cases, and 17 other cases) and were subjected to histological and immunohistochemical investigations. Results: In FWD group, intrapulmonary AQP5 expression was significantly suppressed compared with SWD and CTR; there was no significant difference in AQP5 expression among the other two groups. The same differences in expression were also observed in the kidney. Conclusions: These observations suggest that AQP5 expression in alveolar cells was suppressed by hypotonic water to prevent hemodilution. Moreover, it is possible to hypothesize that in the kidney, with the appearance of hypo-osmotic plasma, AQP5 is hypo-expressed, as a vital reaction, to regulate the renal reabsorption of water. In conclusion, the analysis of renal and intrapulmonary AQP5 expression would be forensically useful for differentiation between FWD and SWD, or between FWD and death due to other causes.

Vasopressin regulation of maternal body fluid balance in pregnancy and lactation: A role for TRPV channels?

Renal water reabsorption increases in pregnancy and lactation to expand maternal blood volume to cope with the cardiovascular demands of the developing fetus and new-born baby. Vasopressin (antidiuretic hormone) promotes renal water reabsorption and its secretion is principally stimulated by body fluid osmolality. Hence, lowered osmolality normally decreases vasopressin secretion. However, despite water retention profoundly reducing osmolality in pregnancy and lactation, vasopressin levels are maintained to drive blood volume expansion. Despite its importance for successful reproduction, the cellular mechanisms that maintain vasopressin secretion in the face of decreased osmolality during pregnancy and lactation are unknown. Vasopressin is secreted by neurons that are intrinsically osmosensitive through expression of N-terminal truncated-transient receptor potential vanilloid-1 channel, ΔN-TRPV1, which is mechanically activated by osmotically-induced cell shrinkage to increase vasopressin neuron activity. Vasopressin neurons also express TRPV4 but the role of TRPV4 in vasopressin neuron function is not well characterised. Here, we summarise our novel evidence showing that TRPV4 forms functional channels with ΔN-TRPV1 that have a greater single-channel conductance compared to channels with ΔN-TRPV1 alone. We propose that upregulation of TRPV4 heteromerisation with ΔN-TRPV1 might maintain vasopressin secretion in pregnancy and lactation to expand blood volume for successful reproduction.

Renal Transplantation in Pure Autonomic Failure.

Renal Transplantation in Pure Autonomic Failure.

AQP2 trafficking in health and diseases: an updated overview.

Renal collecting duct principal cells play a key role in controlling body water balance. Principal cells express the water channels AQP2, AQP3, and AQP4 that mediate renal water reabsorption. AQP3 and AQP4 are expressed at the basolateral membrane constitutively. Conversely, AQP2 is localized in intracellular vesicles and translocates to the plasma membrane under vasopressin action. Stimulation with vasopressin activates the cAMP/PKA signal transduction pathway that induces the redistribution of AQP2 from an intracellular pool to the apical plasma membrane. AQP2 trafficking and function depend on multiple post-translational modifications. Moreover, several proteins control different steps activated by the vasopressin stimulation that triggers the redistribution of the AQP2 vesicles. A-kinase anchoring proteins (AKAPs) together with phosphodiesterases and adenylate cyclases play crucial roles in modulating local changes of cAMP. Soluble N-ethylmaleimide sensitive fusion factor attachment protein receptors (SNARE), cytoskeletal proteins, and the small GTPases of the Rho family regulate the fusion and the endocytotic retrieval of AQP2 vesicles. Abnormal vasopressin signaling and altered AQP2 expression or trafficking can lead to disorders characterized by deregulated mechanisms controlling water homeostasis. This review provides updated data on the molecular signals regulating vasopressin-induced AQP2 trafficking in health and disease.

Chronic activation of vasopressin-2 receptors induces hypertension in Liddle mice by promoting Na+ and water retention.

The renin-angiotensin-aldosterone and arginine vasopressin-V2 receptor-aquaporin-2 (AQP2) systems converge on the epithelial Na+ channel (ENaC) to regulate blood pressure and plasma tonicity. Although it is established that V2 receptors initiate renal water reabsorption through AQP2, whether V2 receptors can also induce renal Na+ retention through ENaC and raise blood pressure remains an open question. We hypothesized that a specific increase in V2 receptor-mediated ENaC activity can lead to high blood pressure. Our approach was to test effects of chronic activation of V2 receptors in Liddle mice, a genetic mouse model of high ENaC activity, and compare differences in ENaC activity, urine Na+ excretion, and blood pressure with control mice. We found that ENaC activity was elevated in Liddle mice and could not be stimulated further by administration of desmopressin (dDAVP), a V2 receptor-specific agonist. In contrast, Liddle mice showed higher levels of expression of AQP2 and aquaporin-3, but they could still respond to dDAVP infusion by increasing phospho-AQP2 expression. With dDAVP infusion, Liddle mice excreted smaller urine volume and less urine Na+ and developed higher blood pressure compared with control mice; this hypertension was attenuated with administration of the ENaC inhibitor benzamil. We conclude that V2 receptors contribute to hypertension in the Liddle mouse model by promoting primary Na+ and concomitant water retention.NEW & NOTEWORTHY Liddle syndrome is a classic model for hypertension from high epithelial Na+ channel (ENaC) activity. In the Liddle mouse model, vasopressin-2 receptors stimulate both ENaC and aquaporin-2, which increases Na+ and water retention to such an extent that hypertension ensues. Liddle mice will preserve plasma tonicity at the expense of a higher blood pressure; these data highlight the inherent limitation in which the kidney must use ENaC as a pathway to regulate both plasma tonicity and blood pressure.

The Immune System in Hypertension: a Lost Shaker of Salt 2021 Lewis K. Dahl Memorial Lecture.

The seminal observations of Dr Lewis Dahl regarding renal mechanisms of hypertension remain highly relevant in light of more recent experiments showing that immune system dysfunction contributes to hypertension pathogenesis. Dr Dahl established that inappropriate salt retention in the kidney plays a central role via Ohm's Law in permitting blood pressure elevation. Nevertheless, inflammatory cytokines whose expression is induced in the early stages of hypertension can alter renal blood flow and sodium transporter expression and activity to foster renal sodium retention. By elaborating these cytokines and reactive oxygen species, myeloid cells and T lymphocytes can connect systemic inflammatory signals to aberrant kidney functions that allow sustained hypertension. By activating T lymphocytes, antigen-presenting cells such as dendritic cells represent an afferent sensing mechanism triggering T cell activation, cytokine generation, and renal salt and water reabsorption. Manipulating these inflammatory signals to attenuate hypertension without causing prohibitive systemic immunosuppression will pose a challenge, but disrupting actions of inflammatory mediators locally within the kidney may offer a path through which to target immune-mediated mechanisms of hypertension while capitalizing on Dr Dahl's key recognition of the kidney's importance in blood pressure regulation.