Urine concentrating ability in cats with hyperthyroidism: Influence of radioiodine treatment, masked azotemia, and iatrogenic hypothyroidism.

BACKGROUND: Hyperthyroid cats often have urine specific gravity (USG) values <1.035. It remains unclear how USG changes after treatment, if USG can be used to predict azotemia after treatment, or how iatrogenic hypothyroidism influences USG values. OBJECTIVES: To determine the proportion of hyperthyroid cats with USG <1.035 vs ≥1.035; if USG changes after treatment; and whether USG <1.035 correlated with unmasking of azotemia or hypothyroidism. ANIMALS: Six hundred fifty-five hyperthyroid cats treated with radioiodine; 190 clinically normal cats. METHODS: Prospective, before-and-after study. Hyperthyroid cats had serum thyroxine, thyroid-stimulating hormone, and creatinine concentrations, and USG measured before and 6 months after successful treatment with radioiodine. RESULTS: Of untreated hyperthyroid cats, USG was ≥1.035 in 346 (52.8%) and <1.035 in 309 (47.2%). After treatment, 279/346 (80.6%) maintained USG ≥1.035, whereas 67/346 (19.4%) became <1.035; 272/309 (88%) maintained USG <1.035, whereas 37/309 (12%) became ≥1.035. Only 22/346 (6.4%) with USG ≥1.035 developed azotemia after treatment, compared with 136/309 (44%) with <1.035 (P < .001). Of cats remaining nonazotemic, 38% had USG <1.035, compared with 20% of normal cats (P < .001). The 137 cats with iatrogenic hypothyroidism had lower USG after treatment than did 508 euthyroid cats (1.024 vs 1.035), but USGs did not change after levothyroxine supplementation. USG <1.035 had high sensitivity (86.1%) but moderate specificity (65.2%) in predicting azotemia after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Hyperthyroidism appears not to affect USG in cats. However, cats with evidence of sub-optimal concentrating ability before radioiodine treatment (USG < 1.035) are more likely to develop azotemia and unmask previously occult chronic kidney disease. Iatrogenic hypothyroidism itself did not appear to affect USG values.

The Idiosyncratic Physiological Traits of the Naked Mole-Rat; a Resilient Animal Model of Aging, Longevity, and Healthspan.

The subterranean-dwelling naked mole-rat (Heterocephalus glaber) is an extremophilic rodent, able to thrive in the harsh underground conditions of sub-Saharan Northeast Africa. This pelage-free mammal exhibits numerous unusual ecophysiological features including pronounced tolerance of thermolability, hypoxia, hypercapnia and noxious substances. As a mammal, the naked mole-rat provides a proof-of-concept that age-related changes in physiology are avoidable. At ages far beyond their expected lifespans given both their body size and/or the timing of early developmental milestones, naked mole-rats fail to exhibit meaningful changes in physiological health or demographic mortality. Lack of physiological deterioration with age is also evident in lean and fat mass, bone quality, and reproductive capacity. Rather, regardless of age, under basal conditions naked mole-rats appear to "idle on low" with their "shields up" as is manifested by low body temperature, metabolic rate, cardiac output and kidney concentrating ability, enabling better protection of organs and cellular function. When needed, they can nevertheless ramp up these functions, increasing cardiac output and metabolism 2-5 fold. Here we review many unusual aspects of their physiology and examine how these attributes facilitate both tolerance of the diverse suite of hostile conditions encountered in their natural milieu as well as contribute to their extraordinary longevity and resistance to common, age-related chronic diseases.

Bird aquaporins: Molecular machinery for urine concentration.

Water conservation is one of the most challenging processes for terrestrial vertebrates and is necessary for their survival. Birds are the only vertebrate animals other than mammals that have the ability to concentrate their urine. Previously, we identified and characterized aquaporins (AQP)1-4 responsible for urine concentration in Japanese quail kidneys. Today, a total of 13 orthologs for these genes have been reported in birds. Bird AQPs can be classified into four subfamilies: 1) Classical AQPs (AQP0-5 and novel member, AQP4-like) that conserve the selectivity filter; 2) aquaglyceroporins (AQP3, 7, 9 and 10) that retain an aspartic acid residue in the second NPA box and expand the pore to accept larger molecules; 3) unorthodox AQPs (AQP11-12) which structurally resemble their mammalian counterparts; 4) AQP8-type, a subfamily that differs from mammalian AQP8. Interestingly, over the course of time, birds lost their mammalian counterpart AQP6 but obtained a novel AQP4-like aquaporin member. In quail and/or chicken kidneys, at least six AQPs are expressed. Quail AQP1 (qAQP1) is expressed in both cortical and medullary proximal tubules but is absent in the descending limb (DL) and the thick ascending limb (TAL), supporting our previous finding that the DL and TAL are water impermeable. AQP2, an arginine vasotocin (AVT)-sensitive water channel, is exclusively expressed in the principal cells of the collecting duct (CD). AQP4 is unlikely to participate in free water resorption from the collecting duct (CD), and only AQP3 may represent an exit pathway for water reabsorbed apically via AQP2. While AQP9 is not expressed in mammalian kidneys, AQP9 was recently found in chicken kidneys. This review summarizes the current knowledge of the structure, function and expression of bird AQPs.

Deletion of Cdh16 Ksp-cadherin leads to a developmental delay in the ability to maximally concentrate urine in mouse.

Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system of the mammalian kidney. The principal aim of the present study was to determine if Ksp-cadherin played a critical role in the development and maintenance of the adult mammalian kidney by generating and evaluating a mouse line deficient in Ksp-cadherin. Ksp-null mutant animals were viable and fertile, and kidneys from both neonates and adults showed no evidence of structural abnormalities. Immunolocalization and Western blot analyses of Na+-K+-ATPase and E-cadherin indicated that Ksp-cadherin is not essential for either the genesis or maintenance of the polarized tubular epithelial phenotype. Moreover, E-cadherin expression was not altered to compensate for Ksp-cadherin loss. Plasma electrolytes, total CO2, blood urea nitrogen, and creatinine levels were also unaffected by Ksp-cadherin deficiency. However, a subtle but significant developmental delay in the ability to maximally concentrate urine was detected in Ksp-null mice. Expression analysis of the principal proteins involved in the generation of the corticomedullary osmotic gradient and the resultant movement of water identified misexpression of aquaporin-2 in the inner medullary collecting duct as the possible cause for the inability of young adult Ksp-cadherin-deficient animals to maximally concentrate their urine. In conclusion, Ksp-cadherin is not required for normal kidney development, but its absence leads to a developmental delay in maximal urinary concentrating ability.NEW & NOTEWORTHY Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system. Using knockout mice, we found that Ksp-cadherin is in fact not required for kidney development despite its high and specific expression along the nephron. However, its absence leads to a developmental delay in maximal urinary concentrating ability.

An AMPK activator as a therapeutic option for congenital nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus (NDI) patients produce large amounts of dilute urine. NDI can be congenital, resulting from mutations in the type-2 vasopressin receptor (V2R), or acquired, resulting from medications such as lithium. There are no effective treatment options for NDI. Activation of PKA is disrupted in both congenital and acquired NDI, resulting in decreased aquaporin-2 phosphorylation and water reabsorption. We show that adenosine monophosphate-activated protein kinase (AMPK) also phosphorylates aquaporin-2. We identified an activator of AMPK, NDI-5033, and we tested its ability to increase urine concentration in animal models of NDI. NDI-5033 increased AMPK phosphorylation by 2.5-fold, confirming activation. It increased urine osmolality in tolvaptan-treated NDI rats by 30%-50% and in V2R-KO mice by 50%. Metformin, another AMPK activator, can cause hypoglycemia, which makes it a risky option for treating NDI patients, especially children. Rats with NDI receiving NDI-5033 showed no hypoglycemia in a calorie-restricted, exercise protocol. Congenital NDI therapy needs to be effective long-term. We administered NDI-5033 for 3 weeks and saw no reduction in efficacy. We conclude that NDI-5033 can improve urine concentration in animals with NDI and holds promise as a potential therapy for patients with congenital NDI due to V2R mutations.

Urine concentration ability is reduced to the same degree in adult dominant polycystic kidney disease compared with other chronic kidney diseases in the same CKD-stage and lower THAN in healthy control subjects - a CASE control study.

BACKGROUND: Concentration of the urine is primarily regulated via vasopressin dependent aquaporin-2 water channels in the apical membrane of kidney principal cells. It is unclear whether urine concentration ability in ADPKD differs from other patients with similar degree of impaired renal function (non-ADPKD patients). The purpose of this case control study was to measure urine concentration ability in ADPKD patients compared to non-ADPKD patients and healthy controls. METHODS: A seventeen hour long water deprivation test was carried out in 17 ADPKD patients (CKD I-IV), 16 non-ADPKD patients (CKD I-IV), and 18 healthy controls. Urine was collected in 4 consecutive periods during water deprivation (12 h, 1 h, 2 h and 2 h, respectively) and analyzed for osmolality (u-Osm), output (UO), fractional excretion of sodium (FENa), aquaporin2 (u-AQP2) and ENaC (u-ENaC). Blood samples were drawn trice (after 13-, 15-, and 17 h after water deprivation) for analyses of osmolality (p-Osm), vasopressin (p-AVP), and aldosterone (p-Aldo). RESULTS: U-Osm was significantly lower and FENa significantly higher in both ADPKD patients and non-ADPKD patients compared to healthy controls during the last three periods of water deprivation. During the same periods, UO was higher and secretion rates of u-AQP2 and u-ENaC were lower and at the same level in the two groups of patients compared to controls. P-AVP and p-Osm did not differ significantly between the three groups. P-Aldo was higher in both groups of patients than in controls. CONCLUSIONS: Urine concentration ability was reduced to the same extent in patients with ADPKD and other chronic kidney diseases with the same level of renal function compared to healthy controls. The lower urine excretion of AQP2 and ENaC suggests that the underlying mechanism may be a reduced tubular response to vasopressin and aldosterone. TRIAL REGISTRATION: Current Controlled Trial NCT04363554 , date of registration: 20.08.2017.

Pax2 and Pax8 Proteins Regulate Urea Transporters and Aquaporins to Control Urine Concentration in the Adult Kidney.

BACKGROUND: As the glomerular filtrate passes through the nephron and into the renal medulla, electrolytes, water, and urea are reabsorbed through the concerted actions of solute carrier channels and aquaporins at various positions along the nephron and in the outer and inner medulla. Proliferating stem cells expressing the nuclear transcription factor Pax2 give rise to renal epithelial cells. Pax2 expression ends once the epithelial cells differentiate into mature proximal and distal tubules, whereas expression of the related Pax8 protein continues. The collecting tubules and renal medulla are derived from Pax2-positive ureteric bud epithelia that continue to express Pax2 and Pax8 in adult kidneys. Despite the crucial role of Pax2 in renal development, functions for Pax2 or Pax8 in adult renal epithelia have not been established. METHODS: To examine the roles of Pax2 and Pax8 in the adult mouse kidney, we deleted either Pax2, Pax8, or both genes in adult mice and examined the resulting phenotypes and changes in gene expression patterns. We also explored the mechanism of Pax8-mediated activation of potential target genes in inner medullary collecting duct cells. RESULTS: Mice with induced deletions of both Pax2 and Pax8 exhibit severe polyuria that can be attributed to significant changes in the expression of solute carriers, such as the urea transporters encoded by Slc14a2, as well as aquaporins within the inner and outer medulla. Furthermore, Pax8 expression is induced by high-salt levels in collecting duct cells and activates the Slc14a2 gene by recruiting a histone methyltransferase complex to the promoter. CONCLUSIONS: These data reveal novel functions for Pax proteins in adult renal epithelia that are essential for retaining water and concentrating urine.

Sodium Handling and Interaction in Numerous Organs.

Salt (NaCl) is a prerequisite for life. Excessive intake of salt, however, is said to increase disease risk, including hypertension, arteriosclerosis, heart failure, renal disease, stroke, and cancer. Therefore, considerable research has been expended on the mechanism of sodium handling based on the current concepts of sodium balance. The studies have necessarily relied on relatively short-term experiments and focused on extremes of salt intake in humans. Ultra-long-term salt balance has received far less attention. We performed long-term salt balance studies at intakes of 6, 9, and 12 g/day and found that although the kidney remains the long-term excretory gate, tissue and plasma sodium concentrations are not necessarily the same and that urinary salt excretion does not necessarily reflect total-body salt content. We found that to excrete salt, the body makes a great effort to conserve water, resulting in a natriuretic-ureotelic principle of salt excretion. Of note, renal sodium handling is characterized by osmolyte excretion with anti-parallel water reabsorption, a state-of-affairs that is achieved through the interaction of multiple organs. In this review, we discuss novel sodium and water balance concepts in reference to our ultra-long-term study. An important key to understanding body sodium metabolism is to focus on water conservation, a biological principle to protect from dehydration, since excess dietary salt excretion into the urine predisposes to renal water loss because of natriuresis. We believe that our research direction is relevant not only to salt balance but also to cardiovascular regulatory mechanisms.

Recomendaciones para el manejo de los pacientes con Enfermedad Renal Crónica o Insuficiencia Renal Aguda durante la epidemia de coronavirus (COVID-19) / Recommendations for the management of patients with Chronic Kidney Disease or Acute Kidney Failure during the coronavirus epidemic

En el marco de la contingencia por COVID 19 que está atravesando nuestro país, es preciso dar Recomendaciones para el manejo de los pacientes con Enfermedad Renal Crónica o Insuficiencia Renal Aguda durante la epidemia de coronavirus (COVID-19)

Tubular Acidification Defect in Adults with Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m2 from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH <5.3 and an increase in urinary ammonium excretion ≥33 µEq/min at one or more of the six time points after furosemide and fludrocortisone administration. RESULTS: Of the participants (median [interquartile range] age of 36 [24-43] years old, 17 women), 12 had a normal and 13 had an abnormal response to the test. Among these 13 participants, nine had normal baseline plasma bicarbonate concentration. Plasma aldosterone was within the normal range for all 13 participants with an abnormal response, making the diagnosis of type 4 tubular acidosis unlikely. The participants with an abnormal response to the test were significantly older, more frequently treated with oral bicarbonate, had a higher plasma uric acid concentration, higher hemolysis activity, lower eGFR, lower baseline plasma bicarbonate concentration, higher urine pH, lower urine ammonium ion excretion, and lower fasting urine osmolality than those with a normal response. Considering both groups, the maximum urinary ammonium ion excretion was positively correlated with fasting urine osmolality (r2=0.34, P=0.002), suggesting that participants with sickle cell disease and lower urine concentration capacity have lower urine acidification capacity. CONCLUSIONS: Among adults with sickle cell disease, impaired urinary acidification capacity attributable to distal tubular dysfunction is common and associated with the severity of hyposthenuria. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_12_10_CJN07830719.mp3.

Partial nephrogenic diabetes insipidus associated with lithium therapy.

A 40-year-old Caucasian man developed excessive thirst and polyuria particularly at night over the preceding 6 months. He had been taking lithium for 16 years for the treatment of bipolar affective disorder. Investigations revealed subnormal maximum urinary concentrating ability after 8 hours of water deprivation and only a borderline response of urine osmolality to exogenous desmopressin given by intramuscular injection. A plasma copeptin concentration was elevated at 23 pmol/L. These results were consistent with partial nephrogenic diabetes insipidus. He was encouraged to increase his water intake as dictated by his thirst. In addition, he received amiloride with some improvement in his symptoms. Clinicians should be aware of the risk of nephrogenic diabetes insipidus with long-term lithium use and seek confirmation by a supervised water deprivation test augmented with a baseline plasma copeptin. If increased water intake is insufficient to control symptoms, amiloride may be considered.

Urine composition in pigs is regulated in both the ureter and the bladder.

The former perception of the urothelium as an impermeable barrier has been revised during the last decade, as increasing evidence of changes in urine composition during its passage of the urinary tract has been presented. Since differences in urothelial permeability between upper and lower urinary tract have been found, our aim is to demonstrate whether changes in urine composition occur during passage through the ureter. We studied consecutive urine samples from both renal pelvises in six pigs and compared them to samples from the bladder and distal ureter. We further sampled urine during storage in the bladder at a fixed volume. All samples were analysed by measuring osmolality and pH, along with the concentration of the following parameters: Na(+), K(+), Cl(-), creatinine, urea. Urine alkalinity increased significantly during passage of the ureter. Creatinine concentration, pH and K(+) increased significantly during the passage from pelvis to the bladder. All other parameters increased non-significantly during the passage to the bladder. The increase in concentration was more pronounced at low concentrations in the pelvis. During storage in the bladder, there was a significant increase in urea concentration. Changes in the composition of urine occur during its passage from the renal pelvis to the bladder and during storage in the bladder. Despite the brief transit time, significant changes in alkalinity were found already during passage through the ureter.

The contribution of collecting duct NOS1 to the concentrating mechanisms in male and female mice.

The collecting duct (CD) concentrates the urine, thereby maintaining body water volume and plasma osmolality within a normal range. The endocrine hormone arginine vasopressin acts in the CD to increase water permeability via the vasopressin 2 receptor (V2R)-aquaporin (AQP) axis. Recent studies have suggested that autocrine factors may also contribute to the regulation of CD water permeability. Nitric oxide is produced predominantly by nitric oxide synthase 1 (NOS1) in the CD and acts as a diuretic during salt loading. The present study sought to determine whether CD NOS1 regulates diuresis during changes in hydration status. Male and female control and CD NOS1 knockout (CDNOS1KO) mice were hydrated (5% sucrose water), water deprived, or acutely challenged with the V2R agonist desmopressin. In male mice, water deprivation resulted in decreased urine flow and increased plasma osmolality, copeptin concentration, and kidney AQP2 abundance independent of CD NOS1. In female control mice, water deprivation reduced urine flow, increased plasma osmolality and copeptin, but did not significantly change total AQP2; however, there was increased basolateral AQP3 localization. Surprisingly, female CDNOS1KO mice while on the sucrose water presented with symptoms of dehydration. Fibroblast growth factor 21, an endocrine regulator of sweetness preference, was significantly higher in female CDNOS1KO mice, suggesting that this was reducing their drive to drink the sucrose water. With acute desmopressin challenge, female CDNOS1KO mice failed to appropriately concentrate their urine, resulting in higher plasma osmolality than controls. In conclusion, CD NOS1 plays only a minor role in urine-concentrating mechanisms.

Site-1 protease-derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capability.

The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V2R) in the collecting duct (CD), critically controls urine concentrating capability. Here, we report that site-1 protease-derived (S1P-derived) soluble (pro)renin receptor (sPRR) participates in regulation of fluid homeostasis via targeting V2R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V2R expression was blunted by a PRR antagonist, PRO20; a PRR-neutralizing antibody; or a S1P inhibitor, PF-429242. In parallel, sPRR release was increased by AVP and reduced by PF-429242. Administration of histidine-tagged sPRR, sPRR-His, stimulated V2R expression and also reversed the inhibitory effect of PF-429242 on the expression induced by AVP. PF-429242 treatment in C57/BL6 mice impaired urine concentrating capability, which was rescued by sPRR-His. This observation was recapitulated in mice with renal tubule-specific deletion of S1P. During the pharmacological or genetic manipulation of S1P alone or in combination with sPRR-His, the changes in urine concentration were paralleled with renal expression of V2R and aquaporin-2 (AQP2). Together, these results support that S1P-derived sPRR exerts a key role in determining renal V2R expression and, thus, urine concentrating capability.

Fragmentar para facilitar y cumplimentar la recogida de orina de 24h / Fragment to facilitate and check 24-hour urine collection

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Lack of urea transporters, UT-A1 and UT-A3, increases nitric oxide accumulation to dampen medullary sodium reabsorption through ENaC.

Although the role of urea in urine concentration is known, the effect of urea handling by the urea transporters (UTs), UT-A1 and UT-A3, on sodium balance remains elusive. Serum and urinary sodium concentration is similar between wild-type mice (WT) and UT-A3 null (UT-A3 KO) mice; however, mice lacking both UT-A1 and UT-A3 (UT-A1/A3 KO) have significantly lower serum sodium and higher urinary sodium. Protein expression of renal sodium transporters is unchanged among all three genotypes. WT, UT-A3 KO, and UT-A1/A3 KO acutely respond to hydrochlorothiazide and furosemide; however, UT-A1/A3 KO fail to show a diuretic or natriuretic response following amiloride administration, indicating that baseline epithelial Na+ channel (ENaC) activity is impaired. UT-A1/A3 KO have more ENaC at the apical membrane than WT mice, and single-channel analysis of ENaC in split-open inner medullary collecting duct (IMCD) isolated in saline shows that ENaC channel density and open probability is higher in UT-A1/A3 KO than WT. UT-A1/A3 KO excrete more urinary nitric oxide (NO), a paracrine inhibitor of ENaC, and inner medullary nitric oxide synthase 1 mRNA expression is ~40-fold higher than WT. Because endogenous NO is unstable, ENaC activity was reassessed in split-open IMCD with the NO donor PAPA NONOate [1-propanamine-3-(2-hydroxy-2-nitroso-1-propylhydrazine)], and ENaC activity was almost abolished in UT-A1/A3 KO. In summary, loss of both UT-A1 and UT-A3 (but not UT-A3 alone) causes elevated medullary NO production and salt wasting. NO inhibition of ENaC, despite elevated apical accumulation of ENaC in UT-A1/A3 KO IMCD, appears to be the main contributor to natriuresis in UT-A1/A3 KO mice.

3D simulation of solutes concentration in urinary concentration mechanism in rat renal medulla.

In this work, a mathematical model was developed to simulate the urinary concentration mechanism. A 3-D geometry was derived based on the detail physiological pictures of rat kidney. The approximate region of each tubule was obtained from the volume distribution of structures based on Walter Pfaller's monograph and Layton's region-based model. Mass and momentum balances were applied to solve for the change in solutes concentration and osmolality. The osmolality of short and long descending nephrons at the end of the outer medulla was obtained to be 530 mOsmol/kgH2O and 802 mOsmol/kgH2O, respectively, which were in acceptable agreement with experimental data. The fluid osmolality of the short and long ascending nephrons was also compatible with experimental data. The osmolality of CD fluid at the end of the inner medulla was determined to be 1198 mOsmol/kgH2O which was close the experimental data (1216 ±â€¯118). Finally, the impact of the position of each tubule on the fluid osmolality and solutes concentration were obvious in the results; for example, short descending limb a1, which is the closest tubule to the collecting duct, had the highest urea concentration in all tubules. This reflects the important effect of the 3D modeling on the precise analysis of urinary concentration mechanism.

Urinary concentrating defect in mice lacking Epac1 or Epac2.

cAMP is a universal second messenger regulating a plethora of processes in the kidney. Two downstream effectors of cAMP are PKA and exchange protein directly activated by cAMP (Epac), which, unlike PKA, is often linked to elevation of [Ca2+]i. While both Epac isoforms (Epac1 and Epac2) are expressed along the nephron, their relevance in the kidney remains obscure. We combined ratiometric calcium imaging with quantitative immunoblotting, immunofluorescent confocal microscopy, and balance studies in mice lacking Epac1 or Epac2 to determine the role of Epac in renal water-solute handling. Epac1-/- and Epac2-/- mice developed polyuria despite elevated arginine vasopressin levels. We did not detect major deficiencies in arginine vasopressin [Ca2+]i signaling in split-opened collecting ducts or decreases in aquaporin water channel type 2 levels. Instead, sodium-hydrogen exchanger type 3 levels in the proximal tubule were dramatically reduced in Epac1-/- and Epac2-/- mice. Water deprivation revealed persisting polyuria, impaired urinary concentration ability, and augmented urinary excretion of Na+ and urea in both mutant mice. In summary, we report a nonredundant contribution of Epac isoforms to renal function. Deletion of Epac1 and Epac2 decreases sodium-hydrogen exchanger type 3 expression in the proximal tubule, leading to polyuria and osmotic diuresis.-Cherezova, A., Tomilin, V., Buncha, V., Zaika, O., Ortiz, P. A., Mei, F., Cheng, X., Mamenko, M., Pochynyuk, O. Urinary concentrating defect in mice lacking Epac1 or Epac2.