RESUMEN
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.
Asunto(s)
Cadherinas/metabolismo , Capacidad de Concentración Renal/fisiología , Riñón/crecimiento & desarrollo , Animales , Acuaporina 2/genética , Acuaporina 2/metabolismo , Cadherinas/genética , Regulación del Desarrollo de la Expresión Génica , Riñón/fisiología , Capacidad de Concentración Renal/genética , Masculino , Ratones , Ratones Noqueados , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
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.
Asunto(s)
Capacidad de Concentración Renal/fisiología , Riñón Poliquístico Autosómico Dominante/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Adulto , Anciano , Aldosterona/sangre , Acuaporina 2/orina , Estudios de Casos y Controles , Canales Epiteliales de Sodio/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Concentración Osmolar , Riñón Poliquístico Autosómico Dominante/metabolismo , Eliminación Renal , Insuficiencia Renal Crónica/metabolismo , Índice de Severidad de la Enfermedad , Sodio/orina , Vasopresinas/sangre , Privación de AguaRESUMEN
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.
Asunto(s)
Acuaporinas/fisiología , Capacidad de Concentración Renal/fisiología , Riñón/fisiología , Proteínas de Transporte de Membrana/fisiología , Factor de Transcripción PAX2/fisiología , Factor de Transcripción PAX8/fisiología , Animales , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Osmorregulación , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX8/genética , Transportadores de UreaRESUMEN
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.
Asunto(s)
Agua Corporal/metabolismo , Sistema Cardiovascular/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Eliminación Renal/fisiología , Sodio/metabolismo , Equilibrio Hidroelectrolítico/fisiología , Animales , Apetito , Ingestión de Líquidos , Metabolismo Energético , Humanos , Ritmo Infradiano/fisiología , Capacidad de Concentración Renal/fisiología , Músculo Esquelético/metabolismo , Natriuresis/fisiología , Cloruro de Sodio Dietético/metabolismo , SedRESUMEN
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.
Asunto(s)
Capacidad de Concentración Renal/fisiología , Túbulos Renales Colectores/metabolismo , ATPasas de Translocación de Protón/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Vasopresinas/metabolismo , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Acuaporina 2/genética , Células Cultivadas , Células Epiteliales , Capacidad de Concentración Renal/efectos de los fármacos , Túbulos Renales Colectores/citología , Túbulos Renales Colectores/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Fragmentos de Péptidos/farmacología , Cultivo Primario de Células , Proproteína Convertasas/antagonistas & inhibidores , Proproteína Convertasas/genética , Proproteína Convertasas/metabolismo , Pirrolidinas/farmacología , Ratas , Receptores de Vasopresinas/genética , Renina/metabolismo , Renina/farmacología , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Urotelio/citología , ATPasas de Translocación de Protón VacuolaresRESUMEN
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.
Asunto(s)
Canales Epiteliales de Sodio/metabolismo , Médula Renal/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Óxido Nítrico/metabolismo , Sodio/metabolismo , Animales , Transporte Iónico/fisiología , Capacidad de Concentración Renal/fisiología , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Noqueados , Transportadores de UreaRESUMEN
Hypertonicity in renal medulla is critical for the kidney to produce concentrated urine. Renal medullary cells have to survive high medullary osmolarity during antidiuresis. Previous study reported that farnesoid X receptor (FXR), a nuclear receptor transcription factor activated by endogenous bile acids, increases urine concentrating ability by up-regulating aquaporin 2 expression in medullary collecting duct cells (MCDs). However, whether FXR is also involved in the maintenance of cell survival of MCDs under dehydration condition and hypertonic stress remains largely unknown. In the present study, we demonstrate that 24-hours water restriction selectively up-regulated renal medullary expression of FXR with little MCD apoptosis in wild-type mice. In contrast, water deprivation caused a massive apoptosis of MCDs in both global FXR gene-deficient mice and collecting duct-specific FXR knockout mice. In vitro studies showed that hypertonicity significantly increased FXR and tonicity response enhancer binding protein (TonEBP) expression in mIMCD3 cell line and primary cultured MCDs. Activation and overexpression of FXR markedly increased cell viability and decreased cell apoptosis under hyperosmotic conditions. In addition, FXR can increase gene expression and nuclear translocation of TonEBP. We conclude that FXR protects MCDs from hypertonicity-induced cell injury very likely via increasing TonEBP expression and nuclear translocation. This study provides insights into the molecular mechanism by which FXR enhances urine concentration via maintaining cell viability of MCDs under hyperosmotic condition.
Asunto(s)
Capacidad de Concentración Renal/fisiología , Médula Renal/citología , Túbulos Renales Colectores/citología , Presión Osmótica/fisiología , Receptores Citoplasmáticos y Nucleares/fisiología , Estrés Fisiológico , Factores de Transcripción/metabolismo , Animales , Regulación de la Expresión Génica , Médula Renal/metabolismo , Túbulos Renales Colectores/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción/genéticaRESUMEN
A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure ( i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules-Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl- cotransporter-that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy.-Maruyama, H., Taguchi, A., Nishikawa, Y., Guili, C., Mikame, M., Nameta, M., Yamaguchi, Y., Ueno, M., Imai, N., Ito, Y., Nakagawa, T., Narita, I., Ishii, S. Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.
Asunto(s)
Enfermedad de Fabry/patología , Enfermedades Renales/patología , Médula Renal/patología , Animales , Modelos Animales de Enfermedad , Enfermedad de Fabry/metabolismo , Capacidad de Concentración Renal/fisiología , Enfermedades Renales/metabolismo , Médula Renal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Poliuria/metabolismo , Poliuria/patología , Sodio/metabolismo , Simportadores de Cloruro de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Trihexosilceramidas/metabolismoRESUMEN
Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle-associated protein). Taken together, our data redefine the AVRs as Tie2 signaling-dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.
Asunto(s)
Angiopoyetina 1/fisiología , Angiopoyetina 2/fisiología , Líquido Extracelular/metabolismo , Capacidad de Concentración Renal/fisiología , Médula Renal/irrigación sanguínea , Receptor TIE-2/fisiología , Angiopoyetina 1/deficiencia , Angiopoyetina 1/genética , Angiopoyetina 2/deficiencia , Angiopoyetina 2/genética , Animales , Tipificación del Cuerpo , Linaje de la Célula , Endotelio Vascular , Genes Reporteros , Edad Gestacional , Proteínas de Homeodominio/análisis , Enfermedades Renales Quísticas/genética , Médula Renal/embriología , Médula Renal/fisiología , Ratones , Ratones Noqueados , Ratones Transgénicos , Miofibroblastos/patología , Ósmosis , Receptor TIE-2/deficiencia , Receptor TIE-2/genética , Circulación Renal , Transducción de Señal , Proteínas Supresoras de Tumor/análisis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/análisisRESUMEN
Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder with renal and extra-renal involvement. The wide spectrum of clinical manifestations is associated to the high genetic heterogeneity. To date 21 genes have been identified in humans and the majority of them encode proteins located on the basal body of the primary cilium. For this reason the disease is has been included among the 'ciliopathies'. The renal involvement is extremely heterogeneous in BBS and is considered the main cause of morbidity and mortality. Recent evidences have suggested that mutations in BBS6, 10 and 12 are associated with a more severe renal dysfunction. The most common renal dysfunction is the urine concentrating defect, even though the underlying mechanism is not completely known. Recently we have demonstrated that hyposthenuria in BBS patients has a renal origin, and depends on desmopessin resistance. The majority of hyposthenuric BBS patients have a combined defect to both concentrate and dilute the urine. The combined defect is associated with a blunted increased urine Aquaproine-2 (u-AQP2) excretion in antidiuresis. A ccordingly, in vitro BBS10 silencing prevented AQP2 trafficking to the apical plasma membrane. However, after long term water restriction hyposthenuric BBS patients showed the same u-AQP2 excretion compared with controls, suggesting that other mechanisms are implicated into the pathogenesis of hyposhtenuria. The complete molecular mechanism underlying hyposhtenuria remains largely unknown in BBS. Whether this defect may represent a predictor factor for poor renal outcome remains to be elucidated.
Asunto(s)
Síndrome de Bardet-Biedl/fisiopatología , Riñón/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Animales , Acuaporina 2/metabolismo , Síndrome de Bardet-Biedl/epidemiología , Síndrome de Bardet-Biedl/genética , Chaperoninas , Cilios/genética , Cilios/patología , Modelos Animales de Enfermedad , Silenciador del Gen , Estudios de Asociación Genética , Chaperoninas del Grupo II/antagonistas & inhibidores , Chaperoninas del Grupo II/genética , Chaperoninas del Grupo II/fisiología , Humanos , Capacidad de Concentración Renal/fisiología , Túbulos Renales Colectores/fisiopatología , Túbulos Renales Colectores/ultraestructura , Ratones , Ratones Noqueados , Ratones Mutantes , Modelos Biológicos , Fenotipo , Transporte de Proteínas , Insuficiencia Renal Crónica/genéticaRESUMEN
OBJECTIVES: To investigate renal concentrating ability after long-term fast-melting oral desmopressin lyophilisate treatment in children with monosymptomatic nocturnal enuresis. METHODS: The present retrospective study involved 58 children (43 boys, 15 girls; aged 6-12 years) with nocturnal enuresis receiving oral desmopressin lyophilisate. After treatment for 4 weeks with a complete response, patients were placed on a reduced dose of 120 µg on alternate days. Moring urine osmolality was measured using urine samples obtained after medication and non-medication dry nights. Patients who experienced ≥1 wet nights/month during alternate-day oral desmopressin lyophilisate treatment or within 6 months after its cessation were assigned to the relapse group, whereas those who experienced <1 wet night/month were assigned to the continued success group. RESULTS: The continued success and relapse groups included 41 and 17 patients, respectively. The mean duration of treatment was 18.5 and 18.3 months in the continued success group and relapse group, respectively. There was no significant difference in morning urine osmolality after medication nights between the continued success and relapse groups; however, morning urine osmolality after non-medication nights was significantly higher in the continued success group than in the relapse group (P < 0.0001). Similarly, nocturnal urine volume was significantly higher in the relapse group than in the continued success group (P = 0.046). CONCLUSIONS: These results suggest that patients receiving long-term oral desmopressin lyophilisate treatment develop increased nocturnal renal concentrating ability, which results in sustained dryness even after treatment cessation.
Asunto(s)
Fármacos Antidiuréticos/uso terapéutico , Desamino Arginina Vasopresina/uso terapéutico , Capacidad de Concentración Renal/efectos de los fármacos , Riñón/fisiopatología , Enuresis Nocturna/tratamiento farmacológico , Administración Oral , Fármacos Antidiuréticos/farmacología , Niño , Desamino Arginina Vasopresina/farmacología , Femenino , Humanos , Riñón/efectos de los fármacos , Capacidad de Concentración Renal/fisiología , Masculino , Enuresis Nocturna/fisiopatología , Concentración Osmolar , Recurrencia , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Orina/químicaRESUMEN
We studied the putative effect of early life experience on the physiological flexibility of metabolic and osmoregulatory traits in the leaf-eared mouse, Phyllotis darwini, an altricial rodent inhabiting seasonal Mediterranean environments. Adult individuals were collected in central Chile and maintained in breeding pairs. Pups were isolated after weaning and acclimated to different temperatures (cold or warm) and water availability (unrestricted and restricted) until adulthood. Subsequently, individuals were re-acclimated to the opposite treatment. Rodents reared in the warm and subjected to water restriction had lower basal metabolic rate (BMR), total evaporative water loss (TEWL) and body mass (Mb) compared with those developing in the cold treatment; nevertheless, individuals subjected to warm temperatures had greater relative medullary thickness (RMT) and urine concentrating ability (UCA). Cold-reared rodents re-acclimated to warm conditions exhibited physiological flexibility of metabolic traits; however, their osmoregulatory attributes did not vary. Conversely, warm-reared rodents re-acclimated to cold had reduced RMT and UCA, but the metabolic traits of these individuals did not change. These results suggest a trade-off between metabolic performance and renal capabilities that might hinder physiological acclimation. Our results support the hypothesis of ontogenetic dependence of short-term acclimation in osmoregulatory and metabolic traits in P. darwini.
Asunto(s)
Aclimatación/fisiología , Osmorregulación/fisiología , Sigmodontinae/crecimiento & desarrollo , Sigmodontinae/fisiología , Temperatura , Animales , Metabolismo Basal/fisiología , Peso Corporal , Femenino , Riñón/anatomía & histología , Capacidad de Concentración Renal/fisiología , Masculino , Pérdida Insensible de Agua/fisiologíaRESUMEN
Whether the tight junction is permeable to water remains highly controversial. Here, we provide evidence that the tricellular tight junction is important for paracellular water permeation and that Ig-like domain containing receptor 1 (ILDR1) regulates its permeability. In the mouse kidney, ILDR1 is localized to tricellular tight junctions of the distal tubules. Genetic knockout of Ildr1 in the mouse kidney causes polyuria and polydipsia due to renal concentrating defects. Microperfusion of live renal distal tubules reveals that they are impermeable to water in normal animals but become highly permeable to water in Ildr1 knockout animals whereas paracellular ionic permeabilities in the Ildr1 knockout mouse renal tubules are not affected. Vasopressin cannot correct paracellular water loss in Ildr1 knockout animals despite normal effects on the transcellular aquaporin-2-dependent pathway. In cultured renal epithelial cells normally lacking the expression of Ildr1, overexpression of Ildr1 significantly reduces the paracellular water permeability. Together, our study provides a mechanism of how cells transport water and shows how such a mechanism may be exploited as a therapeutic approach to maintain water homeostasis.
Asunto(s)
Acuaporinas/fisiología , Capacidad de Concentración Renal/fisiología , Receptores de Superficie Celular/fisiología , Animales , Acuaporina 2/metabolismo , Acuaporinas/metabolismo , Transporte Biológico , Permeabilidad de la Membrana Celular/fisiología , Células Epiteliales/metabolismo , Riñón/metabolismo , Túbulos Renales/metabolismo , Túbulos Renales Distales/metabolismo , Masculino , Ratones , Ratones Noqueados , Receptores de Superficie Celular/metabolismo , Uniones Estrechas/metabolismo , Uniones Estrechas/fisiología , Vasopresinas/metabolismoRESUMEN
Several aquaporin (AQP )-type water channels are expressed in kidney: AQP1 in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2 -6 in the collecting duct; AQP7 in the proximal tubule; AQP8 in the proximal tubule and collecting duct; and AQP11 in the endoplasmic reticulum of proximal tubule cells. AQP2 is the vasopressin-regulated water channel that is important in hereditary and acquired diseases affecting urine-concentrating ability. The roles of AQPs in renal physiology and transepithelial water transport have been determined using AQP knockout mouse models. This chapter describes renal physiologic insights revealed by phenotypic analysis of AQP knockout mice and the prospects for further basic and clinical studies.
Asunto(s)
Acuaporina 1/metabolismo , Riñón/metabolismo , Poliuria/metabolismo , Urea/metabolismo , Agua/metabolismo , Animales , Acuaporina 1/genética , Transporte Biológico , Regulación de la Expresión Génica , Humanos , Riñón/citología , Capacidad de Concentración Renal/fisiología , Ratones , Ratones Noqueados , Concentración Osmolar , Poliuria/genética , Poliuria/patología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
The aim was to quantify the glomerular capillary surface area, the segmental tubular radius, length, and area of single nephrons in mouse and rat kidneys. Multiple 2.5-µm-thick serial Epon sections were obtained from three mouse and three rat kidneys for three-dimensional reconstruction of the nephron tubules. Micrographs were aligned for each kidney, and 359 nephrons were traced and their segments localized. Thirty mouse and thirty rat nephrons were selected for further investigation. The luminal radius of each segment was determined by two methods. The luminal surface area was estimated from the radius and length of each segment. High-resolution micrographs were recorded for five rat glomeruli, and the capillary surface area determined. The capillary volume and surface area were corrected for glomerular shrinkage. A positive correlation was found between glomerular capillary area and proximal tubule area. The thickest part of the nephron, i.e., the proximal tubule, was followed by the thinnest part of the nephron, i.e., the descending thin limb, and the diameters of the seven identified nephron segments share the same rank in the two species. The radius and length measurements from mouse and rat nephrons generally share the same pattern; rat tubular radius-to-mouse tubular radius ratio ≈ 1.47, and rat tubular length-to-mouse tubular length ratio ≈ 2.29, suggesting relatively longer tubules in the rat. The detailed tables of mouse and rat glomerular capillary area and segmental radius, length, and area values may be used to enhance understanding of the associated physiology, including existing steady-state models of the urine-concentrating mechanism.
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Glomérulos Renales/patología , Túbulos Renales Proximales/patología , Nefronas/patología , Animales , Capacidad de Concentración Renal/fisiología , Masculino , Ratones Endogámicos C57BL , Microscopía , Ratas Wistar , Tomografía Computarizada por Rayos X/métodosRESUMEN
The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml·min-1·1.73 m-2 Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling.
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Acuaporina 2/orina , Síndrome de Bardet-Biedl/fisiopatología , Tasa de Filtración Glomerular/fisiología , Riñón/fisiopatología , Uromodulina/orina , Adolescente , Adulto , Síndrome de Bardet-Biedl/orina , Niño , Preescolar , Femenino , Humanos , Capacidad de Concentración Renal/fisiología , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
Introducción: En los últimos años el inicio de diálisis peritoneal (DP) con 3 recambios se ha convertido en una práctica habitual, aunque se dispone de pocos resultados clínicos publicados. Objetivo: Descripción de la experiencia de inicio con DP incremental (DPI) en un centro. Material y métodos: A 46 pacientes en DPI se les realizó seguimiento clínico, analítico y tratamiento, y se estudió su evolución a 2 años. Resultados: A un 25% de los pacientes se les trasplanta en DPI. Tiempo medio de transferencia a DP convencional de 24 meses. La mitad de los pacientes son transferidos por manejo de líquidos. Buena estabilidad clínica y analítica con tasa de peritonitis de un episodio cada 99 meses. Enlentecimiento de la pérdida de función renal residual respecto al período prediálisis (−7,06 vs. −1,58ml/min/año; p=0,0001). Conclusiones: La experiencia en DPI con 3 recambios de inicio es positiva. La mayoría de los pacientes se mantienen estables durante los 2 primeros años, con un enlentecimiento de la pérdida de función renal residual respecto el período prediálisis (AU)
Introduction: Initiation of peritoneal dialysis (PD) with 3 exchanges has become common practice in recent years, despite the lack of published clinical data. Objective: To describe experience with incremental peritoneal dialysis (IPD) at a single site. Material and methods: A total of 46 IPD patients undergoing 2-year clinical, laboratory, treatment and progression follow-up. Results: To 25% of patients were trasplanted on IPD. Mean time on IPD before transfer to conventional PD of 24 months, half of the patients because of fluid balance. Good clinical and biochemical results with a peritonitis rate of one episode per 99 months. There was an improvement in the loss of residual kidney function compared to the pre-dialysis period (−7.06 vs. −1.58ml/min/year;P=.0001). Conclusions: IPD with 3 peritoneal exchanges offers good results. Most patients remain stable during the first 2 years and there is an improvement in the loss of residual kidney function compared to the pre-dialysis period (AU)
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Humanos , Diálisis Peritoneal , Insuficiencia Renal Crónica/terapia , Capacidad de Concentración Renal/fisiología , Tasa de Filtración Glomerular , Pruebas de Función RenalRESUMEN
OBJETIVO: El objetivo de este estudio es analizar las concentraciones en orina (mg/dl) de diferentes factores litogénicos en una muestra de 24 h como predictor de estas alteraciones en lugar de valores absolutos que dependen del volumen de diuresis. MÉTODOS: Desde junio 2014 a mayo 2015 se incluyen un total de 131 pacientes, pertenecientes al Área de Gestión Sanitaria Norte de Almería, con litiasis a los que se indica estudio metabólico. Se realiza estudio de concentraciones de calcio, oxalato, úrico y citrato en orina, junto con cociente calcio/citrato. Se tiene en cuenta la clasificación de hipercalciuria (> 260 mg/24h), hiperuricosuria (> 750 mg/24 h), hiperoxaluria (> 40 mg/24h), hipocitraturia (< 320 mg/24h), hipomagnesuria (< 35 mg/24h). Análisis estadístico con SPSS 17.0. RESULTADOS: Para la concentración de calcio en orina se estima un punto de corte de 12,55 mg/dl con sensibilidad 90% y especificidad 85% con RR de 51,2 (13,9-188,4). En relación a la concentración de oxalato se estima un punto de corte de 1,86 mg/dl con sensibilidad del 91% y especificidad del 84%, con un RR estimado de 67,2 (8,3-540,6). En cuanto a la concentración de úrico en orina se estima un punto de corte de 31,2 mg/dl con una sensibilidad 85% y especificidad 70%, con un RR estimado de 12 (3,8-37,6). En cuanto al citrato, el punto de corte estimado para su concentración fue de 18,8 mg/dl con una sensibilidad y especificidad del 82% y 74% respectivamente, estimando un RR de 13,7 (4,4-42,6). El punto de corte para el magnesio fue de 2,26 mg/dl con sensibilidad 95% y especificidad 78% y RR de 67,6 (11,4-398,3). CONCLUSION: La determinación de concentraciones en orina, en lugar de valores absolutos que dependen en gran medida de la diuresis, parece ser útil a la hora de estimar alteraciones metabólicas clásicas, por lo que deben ser tenidos en cuenta en la evaluación de los pacientes con litiasis
OBJECTIVE: The aim of this study is to analyze urine concentrations (mg/dl) of different lithogenic factors in a sample of 24 h as a predictor of these changes rather than absolute values depend on the volume of diuresis. METHODS: A total of 131 patients from the North Almeria Health Management Area (Spain) with urinary stone disease in whom a metabolic study was indicated were included from June 2014 to May 2015. The concentrations of calcium, oxalate, uric acid, citrate and magnesium were measured in the urine, and the calcium/citrate ratio was calculated. The classifications used were: hypercalciuria (> 260 mg/24h), hyperuricosuria (> 750 mg/24h), hyperoxaluria (> 40 mg/24h), hypocitraturia (> 320 mg/24h) and hypomagnesuria (< 35 mg/24h). The statistical analysis was performed using SPSS 17.0. RESULTS: A cut-off point of 12.55 mg/dl, with a sensitivity of 90% and a specificity of 85% and a relative risk (RR) of 51.2 (13.9-188.4), was estimated for urinary calcium. For oxalate the cut-off point was 1.86 mg/dl, with a sensitivity of 91% and a specificity of 84% with an estimated RR of 67.2 (8.3-540.6). As regards the uric acid concentration in urine, a cut-off point of 31.2 mg/dl was estimated, with a sensitivity of 85% and a specificity of 70% and a RR of 12 (3.8-37.6). For citrate the cut-off point was 18.8 mg/dl, with a sensitivity and specificity of 82% and 74%, respectively, with a RR of 13.7 (4.4- 42.6). The cut-off point for magnesium was 2.26mg/dl with a sensitivity of 95% and specificity of 78%, with a RR of 67.6 (11.4-398.3). CONCLUSION: The determination of urine concentrations, instead of absolute values, depends to a large extent on urine output, appears to be useful when estimating classic metabolic alterations and should be taken into account in the evaluation of patients with urinary stone disease
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Humanos , Masculino , Femenino , Adulto , Capacidad de Concentración Renal/fisiología , Orina/química , Urinálisis/métodos , Litiasis/diagnóstico , Litiasis/terapia , Urolitiasis/diagnóstico , Calcio/análisis , Hipercalciuria/clasificación , Sensibilidad y Especificidad , Diuresis/fisiología , Hiperoxaluria/complicaciones , Hiperoxaluria/diagnóstico , Curva ROC , Oxalato de Calcio/análisis , Ácido Cítrico/análisis , Magnesio/análisisRESUMEN
To investigate age-associated impairments in fluid homeostasis, 4-mo (young) and 32-mo (old) Fischer 344/BN male rats were studied before and after a dietary sodium load. Transferring young rats from a low-sodium (LS) to a high-sodium (HS) diet increased water intake and urine volume by 1.9- and 3.0-fold, respectively, while urine osmolality and plasma aldosterone decreased by 33 and 98%. Concomitantly, adrenocortical angiotensin type 1 receptor (AT1R) density decreased by 35%, and AT1bR mRNA decreased by 39%; no changes were observed in AT1aR mRNA. In contrast, the increase in water intake (1.4-fold) was lower in the old rats, and there was no effect of the HS diet on urine volume or urine osmolality. AT1R densities were 29% less in the old rats before transferring to the HS diet, and AT1R densities were not reduced as rapidly in response to a HS diet compared with the young animals. After 6 days on the HS diet, plasma potassium was lowered by 26% in the old rats, whereas no change was detected in the young rats. Furthermore, while plasma aldosterone was substantially decreased after 2 days on the HS diet in both young and old rats, plasma aldosterone was significantly lower in the old compared with the young animals after 2 wk on the LS diet. These findings suggest that aging attenuates the responsiveness of the adrenocortical AT1R to a sodium load through impaired regulation of AT1bR mRNA, and that this dysregulation contributes to the defects in water and electrolyte homeostasis observed in aging.