Characterization of a functional V1B vasopressin receptor in the male rat kidney: evidence for cross talk between V1B and V2 receptor signaling pathways.

Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2+ concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2+ mobilization and extracellular Ca2+ influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.NEW & NOTEWORTHY Although V1BR mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of V1BR, highlights a cross talk between V1BR and V2 receptor (V2R) in the inner medullary collecting duct, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.

Kinins and Kinin Receptors in Cardiovascular and Renal Diseases.

This review addresses the physiological role of the kallikrein-kinin system in arteries, heart and kidney and the consequences of kallikrein and kinin actions in diseases affecting these organs, especially ischemic and diabetic diseases. Emphasis is put on pharmacological and genetic studies targeting kallikrein; ACE/kininase II; and the two kinin receptors, B1 (B1R) and B2 (B2R), distinguished through the work of Domenico Regoli and his collaborators. Potential therapeutic interest and limitations of the pharmacological manipulation of B1R or B2R activity in cardiovascular and renal diseases are discussed. This discussion addresses either the activation or inhibition of these receptors, based on recent clinical and experimental studies.

Distinct Postprandial Bile Acids Responses to a High-Calorie Diet in Men Volunteers Underscore Metabolically Healthy and Unhealthy Phenotypes.

Bile acids (BAs) regulate dietary lipid hydrolysis and absorption in the proximal intestine. Several studies have highlighted a determinant role of circulating levels and/or metabolism of BAs in the pathogenesis of major cardiometabolic diseases. Whether changes in BA profiles are causative or are consequence of these diseases remains to be determined. Healthy male volunteers (n = 71) underwent a postprandial exploration following consumption of a hypercaloric high fat typical Western meal providing 1200 kcal. We investigated variations of circulating levels of 28 BA species, together with BA synthesis marker 7α-hydroxy-4-cholesten-3-one (C4) over an approximately diurnal 12 h period. Analysis of BA variations during the postprandial time course revealed two major phenotypes with opposite fluctuations, i.e., circulating levels of each individual species of unconjugated BAs were reduced after meal consumption whereas those of tauro- and glyco-conjugated BAs were increased. By an unbiased classification strategy based on absolute postprandial changes in BA species levels, we classified subjects into three distinct clusters; the two extreme clusters being characterized by the smallest absolute changes in either unconjugated-BAs or conjugated-BAs. Finally, we demonstrated that our clustering based on postprandial changes in BA profiles was associated with specific clinical and biochemical features, including postprandial triglyceride levels, BMI or waist circumference. Altogether, our study reveals that postprandial profiles/patterns of BAs in response to a hypercaloric high fat challenge is associated with healthy or unhealthy metabolic phenotypes that may help in the early identification of subjects at risk of developing metabolic disorders.

Medullary and cortical thick ascending limb: similarities and differences.

The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with different composition of the peritubular environment. The TAL plays a critical role in the control of NaCl, water, acid, and divalent cation homeostasis, as illustrated by the consequences of the various monogenic diseases that affect the TAL. It delivers tubular fluid to the distal convoluted tubule and thereby affects the function of the downstream tubular segments. The TAL is commonly considered as a whole. However, many structural and functional differences exist between its medullary and cortical parts. The present review summarizes the available data regarding the similarities and differences between the medullary and cortical parts of the TAL. Both subsegments reabsorb NaCl and have high Na+-K+-ATPase activity and negligible water permeability; however, they express distinct isoforms of the Na+-K+-2Cl- cotransporter at the apical membrane. Ammonia and bicarbonate are mostly reabsorbed in the medullary TAL, whereas Ca2+ and Mg2+ are mostly reabsorbed in the cortical TAL. The peptidic hormone receptors controlling transport in the TAL are not homogeneously expressed along the cortical and medullary TAL. Besides this axial heterogeneity, structural and functional differences are also apparent between species, which underscores the link between properties and role of the TAL under various environments.

Kallikrein/K1, Kinins, and ACE/Kininase II in Homeostasis and in Disease Insight From Human and Experimental Genetic Studies, Therapeutic Implication.

Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.

Effects of hydration on plasma copeptin, glycemia and gluco-regulatory hormones: a water intervention in humans.

PURPOSE: High plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon. METHODS: Thirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water. RESULTS: After acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34-45) (p < 0.001) and remained low the entire test period (4 h). One week of increased water intake led to a 15% reduction (95 CI 5-25) (p = 0.003) of copeptin compared to control week. The greatest reduction occurred among subjects with habitually high copeptin and concentrated urine ("water-responders"). Water-responders had significant water-induced reduction of glucagon, but glucose and insulin were unaffected. CONCLUSIONS: Both acute and 1 week extra water intake potently reduced copeptin concentration. In those with the greatest decline (water-responders), who are typically low drinkers with high baseline copeptin, water induced a reduction in fasting glucagon. Long-term trials assessing the effect of water on glucometabolic traits should focus on low-water drinkers with high copeptin concentration.

Glucagon revisited: Coordinated actions on the liver and kidney.

Glucagon secretion is stimulated by a low plasma glucose concentration. By activating glycogenolysis and gluconeogenesis in the liver, glucagon contributes to maintain a normal glycemia. Glucagon secretion is also stimulated by the intake of proteins, and glucagon contributes to amino acid metabolism and nitrogen excretion. Amino acids are used for gluconeogenesis and ureagenesis, two metabolic pathways that are closely associated. Intriguingly, cyclic AMP, the second messenger of glucagon action in the liver, is released into the bloodstream becoming an extracellular messenger. These effects depend not only on glucagon itself but on the actual glucagon/insulin ratio because insulin counteracts glucagon action on the liver. This review revisits the role of glucagon in nitrogen metabolism and in disposal of nitrogen wastes. This role involves coordinated actions of glucagon on the liver and kidney. Glucagon influences the transport of fluid and solutes in the distal tubule and collecting duct, and extracellular cAMP influences proximal tubule reabsorption. These combined effects increase the fractional excretion of urea, sodium, potassium and phosphates. Moreover, the simultaneous actions of glucagon and extracellular cAMP are responsible, at least in part, for the protein-induced rise in glomerular filtration rate that contributes to a more efficient excretion of protein-derived end products.

Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING: INSERM and Danone Research Centre for Specialized Nutrition.

Renal potassium handling in carriers of the Gly40Ser mutation of the glucagon receptor suggests a role for glucagon in potassium homeostasis.

Plasma potassium concentration (PK ) is tightly regulated. Insulin is known to favor potassium entry into cells. But how potassium leaves the cells later on is not often considered. Previous studies in rats showed that glucagon infusion increased urinary potassium excretion dose-dependently and reversibly. This prompted us to investigate the possible influence of glucagon on potassium handling in humans. We took advantage of the Gly40Ser mutation of the glucagon receptor (GR) that results in a partial loss of function of the GR. In the Olivetti cohort (male workers), 25 subjects who carried this mutation were matched 1:4 to 100 noncarriers for age and weight. Estimated osmolarity of serum and 24-h urine (Sosm and Uosm, respectively) was calculated from the concentrations of the main solutes: [(Na+K)*2 + urea (+glucose for serum)]. Transtubular potassium gradient (TTKG), reflecting the intensity of K secretion in the distal nephron, was calculated as [(urine K/serum K)(Uosm /Sosm )]. There was no significant difference in serum K, or 24-h urine urea, Na and K excretion rates. But urine K concentration was significantly lower in carriers than in noncarriers. Means (interquartile range): 38 (34-43) versus 47 (43-51) mmol/L, P = 0.030. TTKG was also significantly lower in carriers: 4.2 (3.9-4.6) versus 5.0 (4.7-5.2), P = 0.015. This difference remained statistically significant after adjustments for serum insulin and 24-h Na and urea excretions. These results in humans suggest that glucagon stimulates K secretion in the distal nephron. Thus, in conjunction with insulin, glucagon may also participate in K homeostasis by promoting renal K excretion.

Improved protocols for the study of urinary electrolyte excretion and blood pressure in rodents: use of gel food and stepwise changes in diet composition.

Many experimental protocols in rodents require the comparison of groups that are fed different diets. Changes in dietary electrolyte and/or fat content can influence food intake, which can potentially introduce bias or confound the results. Unpalatable diets slow growth or cause weight loss, which is exacerbated by housing the animals in individual metabolic cages or by surgery. For balance studies in mice, small changes in body weight and food intake and low urinary flow can amplify these challenges. Powder food can be administered as gel with the addition of a desired amount of water, electrolytes, drugs (if any), and a small amount of agar. We describe here how the use of gel food to vary water, Na, K, and fat content can reduce weight loss and improve reproducibility of intake, urinary excretion, and blood pressure in rodents. In addition, mild food restriction reduces the interindividual variability and intergroup differences in food intake and associated variables, thus improving the statistical power of an experiment. Finally, we also demonstrate the advantages of using gel food for weight-based drug dosing. These protocols can improve the accuracy and reproducibility of experimental data where dietary manipulations are needed and are especially advisable in rodent studies related to water balance, obesity, and blood pressure.

Genetically increased angiotensin I-converting enzyme alters peripheral and renal vascular reactivity to angiotensin II and bradykinin in mice.

Angiotensin I-converting enzyme (ACE) levels in humans are under strong genetic influence. Genetic variation in ACE has been linked to risk for and progression of cardiovascular and renal diseases. Causality has been documented in genetically modified mice, but the mechanisms underlying causality are not completely elucidated. To further document the vascular and renal consequences of a moderate genetic increase in ACE synthesis, we studied genetically modified mice carrying three copies of the ACE gene (three-copy mice) and littermate wild-type animals (two-copy mice). We investigated peripheral and renal vascular reactivity to angiotensin II and bradykinin in vivo by measuring blood pressure and renal blood flow after intravenous administration and also reactivity of isolated glomerular arterioles by following intracellular Ca2+ mobilization. Carrying three copies of the ACE gene potentiated the systemic and renal vascular responses to angiotensin II over the whole range of peptide concentration tested. Consistently, the response of isolated glomerular afferent arterioles to angiotensin II was enhanced in three-copy mice. In these mice, signaling pathways triggered by endothelial activation by bradykinin or carbachol in glomerular arterioles were also altered. Although the nitric oxide (NO) synthase (NOS)/NO pathway was not functional in arterioles of two-copy mice, in muscular efferent arterioles of three-copy mice NOS3 gene expression was induced and NO mediated the effect of bradykinin or carbachol. These data document new and unexpected vascular consequences of a genetic increase in ACE synthesis. Enhanced vasoconstrictor effect of angiotensin II may contribute to the risk for cardiovascular and renal diseases linked to genetically high ACE levels. NEW & NOTEWORTHY A moderate genetic increase in angiotensin I-converting enzyme (ACE) in mice similar to the effect of the ACE gene D allele in humans unexpectedly potentiates the systemic and renal vasoconstrictor responses to angiotensin II. It also alters the endothelial signaling pathways triggered by bradykinin or carbachol in glomerular efferent arterioles.

Neuroprotective effect of kinin B1 receptor activation in acute cerebral ischemia in diabetic mice.

Activation of the kallikrein-kinin system enhances cardiac and renal tolerance to ischemia. Here we investigated the effects of selective agonists of kinin B1 or B2 receptor (R) in brain ischemia-reperfusion in diabetic and non-diabetic mice. The role of endogenous kinins was assessed in tissue kallikrein deficient mice (TK-/-). Mice underwent 60min-middle cerebral artery occlusion (MCAO), eight weeks after type 1-diabetes induction. Treatment with B1R-, B2R-agonist or saline was started at reperfusion. Neurological deficit (ND), infarct size (IS), brain water content (BWC) were measured at day 0, 1 and 2 after injury. MCAO induced exaggerated ND, mortality and IS in diabetic mice. B2R-agonist increased ND and mortality to 60% and 80% in non-diabetic and diabetic mice respectively, by mechanisms involving hemodynamic failure and renal insufficiency. TK-/- mice displayed reduced ND and IS compared to wild-type littermate, consistent with suppression of B2R activity. B1R mRNA level increased in ischemic brain but B1R-agonist had no effect on ND, mortality or IS in non-diabetic mice. In contrast, in diabetic mice, B1R-agonist tested at two doses significantly reduced ND by 42-52% and IS by 66-71%, without effect on BWC or renal function. This suggests potential therapeutic interest of B1R agonism for cerebral protection in diabetes.

Relationship between Sodium Intake and Water Intake: The False and the True.

BACKGROUND: Generally, eating salty food items increases thirst. Thirst is also stimulated by the experimental infusion of hypertonic saline. But, in steady state, does the kidney need a higher amount of water to excrete sodium on a high than on a low sodium intake? This issue is still controversial. The purpose of this review is to provide examples of how the kidney handles water in relation to salt intake/output. It is based on re-analysis of previously published studies in which salt intake was adjusted to several different levels in the same subjects, and in databases of epidemiologic studies in populations on an ad libitum diet. Summary and Key Messages: These re-analyses allow us to draw the following conclusions: (1) In a steady state situation, the urine volume (and thus the fluid intake) remains unchanged over a large range of sodium intakes. The adaptation to a higher sodium excretion rests only on changes in urinary sodium concentration. However, above a certain limit, this concentration cannot increase further and the urine volume may then increase. (2) In population studies, it is not legitimate to assume that sodium is responsible for changes in urine volume, since people who eat more sodium also eat more of other nutrients leading to an increase in the excretion of potassium, urea and other solutes, besides sodium. (3) After an abrupt increase in sodium intake, fluid intake is increased in the first few days, but urine volume does not change. The extra fluid drunk is responsible for an increase in body weight.

Antagonism of vasopressin V2 receptor improves albuminuria at the early stage of diabetic nephropathy in a mouse model of type 2 diabetes.

AIMS: Vasopressin is increased in diabetes and was shown to contribute to development of diabetic nephropathy through V2 receptor (V2R) activation in an experimental model of type 1 diabetes. The role of V2R in type 2 diabetes remains undocumented. This study addresses the issue in a mouse model of type 2 diabetes. METHODS: Male obese diabetic db/db mice were treated for 12weeks with a selective V2R antagonist (SR121463) and compared to non-treated db/db and non-diabetic db/m mice. All animals were previously uninephrectomized. RESULTS: The V2R antagonist did not alter glycemia or glycosuria in db/db mice. It induced a two-fold increase in urine output and a 52% decrease in urine osmolality compared to non-treated db/db mice. After four weeks of treatment urinary albumin to creatinine ratio was 50% lower in treated mice compared to non-treated mice, and remained significantly lower until end of experiment. Glomerular filtration rate increased significantly over time in non-treated db/db mice but remained stable in treated mice. CONCLUSIONS: This study shows that vasopressin contributes to albuminuria and glomerular hyperfiltration via V2R in a mouse model of type 2 diabetes. It documents causality behind the association of vasopressin with renal disease observed in diabetic patients.

Acute and chronic hyperglycemic effects of vasopressin in normal rats: involvement of V1A receptors.

Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V1A and V1B receptors (R) are expressed in the liver and pancreatic islets, respectively. The present study was designed to determine the impact of different levels of circulating AVP on glucose homeostasis in normal Sprague-Dawley rats, as well as the respective roles of V1AR and V1BR. We showed that acute injection of AVP induces a dose-dependent increase in glycemia. Pretreatment with a selective V1AR antagonist, but not a V1BR antagonist, dose-dependently prevented the rise in glycemia. V1BR antagonism did not modify the hyperinsulinemic response, resulting from AVP-induced hyperglycemia, but enhanced the fall in glucagonemia. Acute administration of selective V1AR or V1BR agonists confirmed the involvement of V1AR in the hyperglycemic effect of AVP. In chronic experiments, AVP levels were altered in both directions. Sustained AVP infusion through implantable minipumps induced a time-dependent increase in fasting glycemia, whereas lowering endogenous AVP by increasing water intake had no effect. After 4 wk of AVP infusion, the rise in glycemia amounted to 1.1 mmol/l (P < 0.01) without significant change in insulinemia. This effect was attenuated by cotreatment with a V1AR antagonist. Similar results were observed in lean Zucker rats. These findings demonstrate for the first time a causal link between chronic high AVP and hyperglycemia through V1AR activation and, thus, provide a pathophysiological explanation for the relationship observed in human cohorts between the AVP-hydration axis and the risk of diabetes.

Plasma Copeptin, Kidney Outcomes, Ischemic Heart Disease, and All-Cause Mortality in People With Long-standing Type 1 Diabetes.

OBJECTIVE: Plasma copeptin, a surrogate for vasopressin, has been associated with a decline in renal function and albuminuria in population-based studies as well as with progression of diabetic nephropathy in people with type 2 diabetes. We assessed the risk of kidney and coronary events and all-cause mortality associated with plasma copeptin in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: Plasma copeptin was measured in baseline samples of the GENEDIAB (n = 398; 56% male; mean ± SD age 45 ± 12 years and diabetes duration 28 ± 10 years) and GENESIS (n = 588; 52% male; age 42 ± 11 years; diabetes duration 27 ± 9 years) cohorts. Follow-up data were available for 218 GENEDIAB and 518 GENESIS participants. Median duration of follow-up was 10.2 and 5.0 years, respectively. RESULTS: Upper sex-specific tertiles of copeptin were associated with a higher incidence of end-stage renal disease (ESRD) during follow-up (hazard ratio [HR] for third vs. first tertile 26.5 [95% CI 8.0-163.3; P < 0.0001]; analysis in pooled cohorts adjusted for age, sex, duration of diabetes, and cohort membership). The highest tertile of copeptin was also associated with incidence of myocardial infarction or coronary revascularization (HR 2.2 [95% CI 1.2-4.0]; P = 0.01) and all-cause mortality (HR 3.3 [95% CI 1.8-6.5]; P < 0.0001) during follow-up. CONCLUSIONS: Plasma copeptin is a predictor for the risk of ESRD, coronary heart disease, and all-cause mortality in people with type 1 diabetes. Results are consistent with data from experimental and epidemiological studies, suggesting that high circulating levels of vasopressin are deleterious to renal function.

Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications.

Genetic and pharmacological studies, clinical and experimental, focused on kallikrein-K1, kinin receptors and ACE/kininase II suggest that kinin release in the settings of ischemia or diabetes reduces organ damage, especially in the heart and kidney. Kinin bioavailability may be a limiting factor for efficacy of current kinin-potentiating drugs, like ACE inhibitors. Primary activation of kinin receptors by prototypic pharmacological agonists, peptidase-resistant, selective B1 or B2, displays therapeutic efficacy in experimental cardiac and peripheral ischemic and diabetic diseases. B1R agonism was especially efficient in diabetic animals and had no unwanted effects. Clinical development of kinin receptor agonists may be warranted.

Glucagon actions on the kidney revisited: possible role in potassium homeostasis.

It is now recognized that the metabolic disorders observed in diabetes are not, or not only due to the lack of insulin or insulin resistance, but also to elevated glucagon secretion. Accordingly, selective glucagon receptor antagonists are now proposed as a novel strategy for the treatment of diabetes. However, besides its metabolic actions, glucagon also influences kidney function. The glucagon receptor is expressed in the thick ascending limb, distal tubule, and collecting duct, and glucagon regulates the transepithelial transport of several solutes in these nephron segments. Moreover, it also influences solute transport in the proximal tubule, possibly by an indirect mechanism. This review summarizes the knowledge accumulated over the last 30 years about the influence of glucagon on the renal handling of electrolytes and urea. It also describes a possible novel role of glucagon in the short-term regulation of potassium homeostasis. Several original findings suggest that pancreatic α-cells may express a "potassium sensor" sensitive to changes in plasma K concentration and could respond by adapting glucagon secretion that, in turn, would regulate urinary K excretion. By their combined actions, glucagon and insulin, working in a combinatory mode, could ensure an independent regulation of both plasma glucose and plasma K concentrations. The results and hypotheses reviewed here suggest that the use of glucagon receptor antagonists for the treatment of diabetes should take into account their potential consequences on electrolyte handling by the kidney.

Hydration and Chronic Kidney Disease Progression: A Critical Review of the Evidence.

We performed a comprehensive literature review to examine evidence on the effects of hydration on the kidney. By reducing vasopressin secretion, increasing water intake may have a beneficial effect on renal function in patients with all forms of chronic kidney disease (CKD) and in those at risk of CKD. This potential benefit may be greater when the kidney is still able to concentrate urine (high fluid intake is contraindicated in dialysis-dependent patients). Increasing water intake is a well-accepted method for preventing renal calculi, and current evidence suggests that recurrent dehydration and heat stress from extreme occupational conditions is the most probable cause of an ongoing CKD epidemic in Mesoamerica. In polycystic kidney disease (PKD), increased water intake has been shown to slow renal cyst growth in animals via direct vasopressin suppression, and pharmacologic blockade of renal vasopressin-V2 receptors has been shown to slow cyst growth in patients. However, larger clinical trials are needed to determine if supplemental water can safely slow the loss of kidney function in PKD patients.

Plasma Copeptin, AVP Gene Variants, and Incidence of Type 2 Diabetes in a Cohort From the Community.

CONTEXT: Experimental data support a role for vasopressin in metabolic disorders. OBJECTIVE: We investigated associations of plasma copeptin, a surrogate of vasopressin, and of allelic variations in the arginine vasopressin-neurophysin II gene with insulin secretion, insulin sensitivity, and the risk for impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM). DESIGN, SETTING, AND PARTICIPANTS: We studied 5110 unrelated French men and women from a prospective cohort of the general population (Data from Epidemiological Study on the Insulin Resistance Syndrome cohort, 9-y follow-up). Six single nucleotide polymorphisms were genotyped. MAIN OUTCOME MEASURE: Incidence of IFG or T2DM during follow-up. RESULTS: The incidence of hyperglycemia (IFG/T2DM) during follow-up by quartiles of baseline plasma copeptin was 11.0% (Q1), 14.5% (Q2), 17.0% (Q3), and 23.5% (Q4), log-rank test P = .003. Participants in the upper quartile of plasma copeptin had significantly lower insulin sensitivity (homeostasis model assessment index) at baseline and during follow-up, as compared with other participants. Cox proportional hazards regression analyses showed significant associations of the CC genotype of rs6084264, the TT genotype of rs2282018, the C-allele of rs2770381, and the CC genotype of rs1410713 with the incidence of hyperglycemia. The genotypes associated with an increased risk of hyperglycemia were also associated with increased plasma copeptin in men but not in women. CONCLUSIONS: High plasma copeptin was associated with reduced insulin sensitivity and an increased risk for IFG/T2DM diabetes in this community-based cohort. Moreover, in men, allelic associations support a causal role for vasopressin in these disorders.