RESUMO
Vasopressin has many physiological actions in addition to its well-defined role in the control of fluid homeostasis and urine concentration. An increasing body of evidence suggests that the vasopressin-hydration axis plays a role in glucose homeostasis. This review summarizes the knowledge accumulated over the last decades about the influence of vasopressin in the short-term regulation of glycaemia. It describes the possible role of this hormone through activation of V1a and V1b receptors on liver and pancreas functions and on the hypothalamic-pituitary-adrenal axis. Moreover, we report recent in vivo studies demonstrating the role of vasopressin in the long-term regulation of glycaemia. Indeed, V1a- or double-V1aV1b-receptor knockout mice display significant changes in the glucose and lipid metabolism. In rats, sustained high V1aR activation increases basal glycaemia and aggravates glucose intolerance in obese rats. Finally, the translation from animal findings to human was evidenced by epidemiological and genetic studies that showed that high vasopressin level is a risk factor for hyperglycaemia, metabolic disorders and diabetes.
Assuntos
Doenças Metabólicas/fisiopatologia , Vasopressinas/fisiologia , Animais , Glicemia/fisiologia , Glucose/metabolismo , Glicopeptídeos/sangue , Glicopeptídeos/fisiologia , Homeostase/fisiologia , Humanos , Obesidade/fisiopatologia , Ratos , Receptores de Vasopressinas/fisiologiaRESUMO
Study of mice rendered deficient in tissue kallikrein (TK) by gene inactivation and human subjects partially deficient in TK activity as consequence of an active site mutation has allowed recognising the physiological role of TK and its peptide products kinins in arterial function and in vasodilatation, in both species. TK appears as the major kinin forming enzyme in arteries, heart and kidney. Non-kinin mediated actions of TK may occur in epithelial cells in the renal tubule. In basal condition, TK deficiency induces mild defective phenotypes in the cardiovascular system and the kidney. However, in pathological situations where TK synthesis is typically increased and kinins are produced, TK deficiency has major, deleterious consequences. This has been well documented experimentally for cardiac ischaemia, diabetes renal disease, peripheral ischaemia and aldosterone-salt induced hypertension. These conditions are all aggravated by TK deficiency. The beneficial effect of ACE/kininase II inhibitors or angiotensin II AT1 receptor antagonists in cardiac ischaemia is abolished in TK-deficient mice, suggesting a prominent role for TK and kinins in the cardioprotective action of these drugs. Based on findings made in TK-deficient mice and additional evidence obtained by pharmacological or genetic inactivation of kinin receptors, development of novel therapeutic approaches relying on kinin receptor agonism may be warranted.
Assuntos
Calicreínas Teciduais/genética , Calicreínas Teciduais/metabolismo , Aldosterona/metabolismo , Animais , Pressão Sanguínea , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Isquemia/metabolismo , Isquemia/fisiopatologia , Rim/metabolismo , Cininas/química , Camundongos , Camundongos Transgênicos , Mutação , Fenótipo , Polimorfismo GenéticoRESUMO
BACKGROUND: High plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin pro-hormone, has been associated with the metabolic syndrome (MetS), diabetes mellitus (DM) development and nephropathy. Here we tested whether elevated copeptin level is associated with later development of the MetS, its individual components and microalbuminuria. METHODS: We analysed copeptin at baseline (1991-1994) in the population-based Malmö Diet and Cancer Study cardiovasular cohort and re-examined 2064 subjects 15.8 years later (mean age 72.8 years, 59% women) with oral glucose tolerance test and measurement of MetS and its individual components. RESULTS: After age and sex adjustment, increasing quartiles of copeptin at baseline (the lowest quartile as reference) were associated with MetS (P for trend=0.008), incident abdominal obesity (P for trend=0.002), DM (P for trend=0.001) and microalbuminuria (P for trend=0.002). After additional adjustment for all the MetS components at baseline, increasing copeptin quartiles predicted incident abdominal obesity (odds ratios 1.55, 1.30 and 1.59; P for trend=0.04), DM (odds ratios 1.18, 1.32 and 1.46; P for trend=0.04) and microalbuminuria (odds ratios 1.05, 1.08 and 1.65; P for trend=0.02) but not MetS (P for trend=0.19) at the reexamination. Further, the relationship between copeptin and microalbuminuria was independent of baseline C-reactive protein, incident DM and incident hypertension. CONCLUSION: Copeptin independently predicts DM and abdominal obesity but not the cluster of MetS. Apart from predicting DM and abdominal obesity, elevated copeptin signals increased risk of microalbuminuria. Interestingly, the association between copeptin and later microalbuminuria was independent of both prevalent and incident DM and hypertension. Our findings suggest a relationship between a dysregulated vasopressin system and cardiometabolic risk, which could have implications for risk assessment and novel preventive treatments.
Assuntos
Albuminúria/metabolismo , Arginina Vasopressina/metabolismo , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/metabolismo , Glicopeptídeos/metabolismo , Síndrome Metabólica/metabolismo , Neoplasias/metabolismo , Obesidade Abdominal/metabolismo , Distribuição por Idade , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Albuminúria/epidemiologia , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Obesidade Abdominal/epidemiologia , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Fatores de Risco , Distribuição por Sexo , Suécia/epidemiologia , Fatores de TempoRESUMO
Ischemic disease represents the new epidemic worldwide. Animal models of ischemic disease are useful because they can help us to understand the underlying pathogenetic mechanisms and develop new therapies. The present review article summarizes the results of a consensus conference on the status and future development of experimentation in the field of cardiovascular medicine using murine models of peripheral and myocardial ischemia. The starting point was to recognize the limits of the approach, which mainly derive from species- and disease-related differences in cardiovascular physiology. For instance, the mouse heart beats at a rate 10 times faster than the human heart. Furthermore, healing processes are more rapid in animals, as they rely on mechanisms that may have lost relevance in man. The main objective of the authors was to propose general guidelines, diagnostic end points and relevance to clinical problems.
Assuntos
Experimentação Animal , Modelos Animais de Doenças , Extremidades/irrigação sanguínea , Oclusão de Enxerto Vascular/fisiopatologia , Isquemia/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Experimentação Animal/ética , Experimentação Animal/legislação & jurisprudência , Animais , Aterosclerose/cirurgia , Comorbidade , Consenso , Diabetes Mellitus Tipo 1/fisiopatologia , Determinação de Ponto Final , Oclusão de Enxerto Vascular/terapia , Guias como Assunto , Humanos , Isquemia/terapia , Camundongos , Isquemia Miocárdica/terapia , Medicina Regenerativa , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Especificidade da Espécie , Veias/transplante , CicatrizaçãoRESUMO
Renal volume regulation is modulated by the action of cyclooxygenases (COX) and the resulting generation of prostanoids. Epithelial expression of COX isoforms in the cortex directs COX-1 to the distal convolutions and cortical collecting duct, and COX-2 to the thick ascending limb. Partly colocalized are prostaglandin E synthase (PGES), the downstream enzyme for renal prostaglandin E(2) (PGE(2)) generation, and the EP receptors type 1 and 3. COX-1 and related components were studied in two kidney-one clip (2K1C) Goldblatt hypertensive rats with combined chronic ANG II or bradykinin B(2) receptor blockade using candesartan (cand) or the B(2) antagonist Hoechst 140 (Hoe). Rats (untreated sham, 2K1C, sham + cand, 2K1C + cand, sham + Hoe, 2K1C + Hoe) were treated to map expression of parameters controlling PGE(2) synthesis. In 2K1C, cortical COX isoforms did not change uniformly. COX-2 changed in parallel with NO synthase 1 (NOS1) expression with a raise in the clipped, but a decrease in the nonclipped side. By contrast, COX-1 and PGES were uniformly downregulated in both kidneys, along with reduced urinary PGE(2) levels, and showed no clear relations with the NO status. ANG II receptor blockade confirmed negative regulation of COX-2 by ANG II but blunted the decrease in COX-1 selectively in nonclipped kidneys. B(2) receptor blockade reduced COX-2 induction in 2K1C but had no clear effect on COX-1. We suggest that in 2K1C, COX-1 and PGES expression may fail to oppose the effects of renovascular hypertension through reduced prostaglandin signaling in late distal tubule and cortical collecting duct.
Assuntos
Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Córtex Renal/enzimologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo , Pressão Sanguínea/fisiologia , Bradicinina/análogos & derivados , Bradicinina/farmacologia , GMP Cíclico/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/urina , Modelos Animais de Doenças , Túbulos Renais Coletores/enzimologia , Túbulos Renais Distais/enzimologia , Alça do Néfron/enzimologia , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP1 , Receptores de Prostaglandina E Subtipo EP3 , Instrumentos Cirúrgicos , Tetrazóis/farmacologiaRESUMO
Previous studies revealed that chronic (days) vasopressin treatment stimulates amiloride-sensitive sodium transport in isolated renal cortical collecting ducts and increases the abundance of beta- and gamma-subunits of the epithelial sodium channel (ENaC) in the kidney. The aim of the present work was to investigate in vivo the cellular basis of these effects. The long-term effect of V2 vasopressin agonist (1-deamino-8-D-arginine vasopressin (dDAVP)) on the abundance and subcellular localization of ENaC along the rat renal collecting system was determined by immunohistochemistry and laser confocal microscopy. Moreover, we studied by real-time reverse transcriptase-polymerase chain reaction the effect of vasopressin on proteins implicated in the regulation of ENaC (Nedd4-2, prostasin, Sgk1). After 5 days of administration, dDAVP markedly increased the intracellular pool of the beta- and gamma-ENaC subunits in the principal cells, with an increasing gradient from connecting tubule to the outer medullary collecting duct, but did not increase any subunit at the cell surface. The apical immunostaining of ENaC increased in response to sodium restriction, as expected, but dDAVP did not further enhance this apical labelling. dDAVP increased the gene expression of prostasin in the cortex but not that of Nedd4-2 and Sgk1. These findings suggest that the previously reported increase in sodium transport induced by sustained stimulation of vasopressin V2 receptor is probably mediated by other mechanism than an increase in the apical density of ENaC.
Assuntos
Túbulos Renais Coletores/química , Canais de Sódio/análise , Vasopressinas/farmacologia , Aldosterona/análise , Aldosterona/sangue , Animais , Desamino Arginina Vasopressina/farmacologia , Ingestão de Líquidos , Canais Epiteliais de Sódio , Imunofluorescência , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Córtex Renal/química , Masculino , Microscopia Confocal , Ratos , Ratos Brattleboro , Ratos Sprague-Dawley , Receptores de Vasopressinas/análise , Receptores de Vasopressinas/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/análise , Serina Endopeptidases/genética , Sódio na Dieta/farmacologia , Fatores de Tempo , Vasopressinas/sangueRESUMO
Water balance depends essentially on fluid intake and urine excretion. Mild dehydration and the consequent hypertonicity of the extracellular fluid induce an increase in vasopressin secretion, thus stimulating urine concentrating processes and the feeling of thirst. The osmotic threshold for the release of vasopressin is lower than that for thirst and also shows appreciable individual variation. Sustained high levels of vasopressin and low hydration induce morphological and functional changes in the kidney. However, they could also be risk factors in several renal disorders, such as chronic renal failure, diabetic nephropathy and salt-sensitive hypertension.
Assuntos
Desidratação/fisiopatologia , Rim/fisiologia , Vasopressinas/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia , Animais , Humanos , Capacidade de Concentração Renal , Nefropatias/etiologia , Ratos , Sede/efeitos dos fármacos , Sede/fisiologia , Micção/efeitos dos fármacos , Micção/fisiologia , Vasopressinas/farmacologiaRESUMO
Diabetic nephropathy is a major risk factor for end-stage renal disease and cardiovascular diseases and has a marked genetic component. A common variant (D allele) of the angiotensin I-converting enzyme (ACE) gene, determining higher enzyme levels, has been associated with diabetic nephropathy. To address causality underlying this association, we induced diabetes in mice having one, two, or three copies of the gene, normal blood pressure, and an enzyme level range (65-162% of wild type) comparable to that seen in humans. Twelve weeks later, the three-copy diabetic mice had increased blood pressures and overt proteinuria. Proteinuria was correlated to plasma ACE level in the three-copy diabetic mice. Thus, a modest genetic increase in ACE levels is sufficient to cause nephropathy in diabetic mice.
Assuntos
Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Peptidil Dipeptidase A/sangue , Albuminúria/genética , Animais , Pressão Sanguínea/genética , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/enzimologia , Nefropatias Diabéticas/enzimologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Peptidil Dipeptidase A/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Vasopressin is known to acutely stimulate sodium transport in the renal collecting duct. We investigated the long-term regulation by vasopressin of the epithelial sodium channel (ENaC) in the rat kidney. Five-day infusion of dDAVP (a V(2) receptor agonist) to Brattleboro rats lacking vasopressin induced a marked increase in beta- and gamma-subunit ENaC mRNA levels in the renal cortex (beta, 85%; gamma, 100%), with no change in alpha-ENaC mRNA. Expression of beta- and gamma-ENaC mRNAs was also enhanced in lung (beta, 49%; gamma, 33%) but not in distal colon (an organ devoid of V(2) receptors). Similar results were obtained in Sprague Dawley rats after either partial water restriction or dDAVP infusion for 5 days. Transepithelial voltage and transepithelial sodium and water net fluxes were measured in isolated perfused cortical collecting ducts of Brattleboro rats. Acute addition of 2x10(-10) mol/L dDAVP to the bath increased sodium and water fluxes in the same proportion, and to a far greater extent in dDAVP-infused than in control Brattleboro rats (change in Na(+) net flux, 337+/-30 versus 49+/-11 pmol. min(-1). mm(-1), respectively; P<0.001). These effects were abolished by amiloride. Extrarenal water losses, partly originating from the lung, were reduced by high plasma vasopressin level. This study shows that vasopressin increases sodium transport in the renal collecting duct and probably in the lung, through a differential transcriptional regulation of ENaC subunits. This effect is followed by isoosmotic water reabsorption and likely contributes to the process of water conservation. It could lead to less efficient sodium excretion, however, and thus participate in some forms of salt-sensitive hypertension.
Assuntos
Desamino Arginina Vasopressina/farmacologia , Túbulos Renais Coletores/metabolismo , Pulmão/metabolismo , Fármacos Renais/farmacologia , Canais de Sódio/biossíntese , Sódio/metabolismo , Animais , Desamino Arginina Vasopressina/administração & dosagem , Canais Epiteliais de Sódio , Transporte de Íons/efeitos dos fármacos , Masculino , RNA Mensageiro/biossíntese , Ratos , Ratos Brattleboro , Ratos Sprague-Dawley , Fármacos Renais/administração & dosagem , Canais de Sódio/genética , Ativação Transcricional , Regulação para Cima , Equilíbrio HidroeletrolíticoRESUMO
Differences involving serine residues in the sequence of the carboxyl-terminal tail of type 1 angiotensin II (Ang II) receptor subtypes AT(1A) and AT(1B) suggest differences in desensitization ability. We examined the Ang II-induced homologous desensitization patterns of both receptor subtypes in freshly isolated renal structures: glomerulus (Glom), afferent arteriole, and cortical thick ascending limb (CTAL), whose content in each subtype mRNA is different, by measuring variations in intracellular calcium concentration. A preexposure to a maximal dose of Ang II, followed by a second application of the same concentration, induced: 1) a complete desensitization in Glom, where AT(1A) and AT(1B) mRNAs were expressed in similar proportions, and 2) no or partial desensitization in afferent arteriole and CTAL, where AT(1A) mRNA was predominant. In the absence of nephron structure containing only AT(1B) mRNA, we studied rat anterior pituitary cells that exhibit high content in this subtype and observed that desensitization was not complete. In Glom, CTAL, and pituitary cells, desensitization proceeded in a dose-dependent manner. In Glom and CTAL, desensitization occurred via a PKC-independent mechanism. These results suggest that desensitization does not depend on the nature of Ang II receptor subtype but either on the proportion of each subtype in a given cell and/or on cell specific type. This could allow adaptive biological responses to Ang II appropriate to the specific function of a given cell type.
Assuntos
Angiotensina II/farmacologia , Rim/metabolismo , Receptores de Angiotensina/metabolismo , Animais , Arteríolas/metabolismo , Cálcio/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Membranas Intracelulares/metabolismo , Glomérulos Renais/citologia , Glomérulos Renais/metabolismo , Alça do Néfron/citologia , Alça do Néfron/metabolismo , Masculino , Concentração Osmolar , Adeno-Hipófise/citologia , Adeno-Hipófise/metabolismo , Proteína Quinase C/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina , Receptores de Angiotensina/efeitos dos fármacosRESUMO
BACKGROUND: In a previous study we observed that acute administration of the selective antagonist of vasopressin (AVP) V2 receptors, SR 121463A (SR), aggravated the symptoms of diabetes insipidus (DI) in homozygous Brattleboro rats (an AVP-deficient strain). The present study investigates in more details the acute and chronic effects of SR in DI rats. METHODS AND RESULTS: In experiment A, different groups of rats received acute i.p. injections of SR (0.001-10 mg/kg) or vehicle alone, and urine was collected for the next 24 h. SR dose-dependently increased urine flow rate and decreased urine osmolality with no significant change in solute excretion, thus confirming a pure 'aquaretic' effect. In experiments B and C, the chronic effects of orally administered SR were evaluated over 8 days in Brattleboro DI rats (experiment B, 1 mg/kg/day) and in adult Sprague-Dawley rats with normal AVP secretion (experiment C, 3 mg/kg/day). In DI rats, the aquaretic effects of SR persisted with the same intensity over the 8 days. In Sprague-Dawley rats, SR induced a sustained, stable aquaretic effect and also increased non-renal water losses, suggesting an effect of AVP on water conservation in extrarenal sites. Because oxytocin (OT) synthesis is elevated in DI rats and OT is known to bind to V2 receptors, we evaluated the antidiuretic effects of OT in DI rats in experiment D. Chronic infusion of OT (3 microg/kg/h, i.p.) induced a marked antidiuresis, and acute SR (1 mg/kg) in OT-treated DI rats completely abolished this antidiuretic effect, thus indicating that it was due to binding of OT to V2 receptors. CONCLUSION: (i) SR is a potent orally active aquaretic and induces stable effects during 1 week in rats with or without endogenous AVP secretion. (ii) Significant V2 receptor-mediated water reabsorption occurs in collecting ducts of Brattleboro DI rats because their usual urine osmolality is about twofold higher than the minimum observed during SR-induced maximum diuresis. (iii) This V2 agonism could be mediated in part by OT binding to V2 receptors. Small amounts of endogenous AVP, known to be produced by adrenal and testis in DI rats, could also contribute to this V2 agonism, as well as a possible constitutive activation of the V2 receptors. (iv) In normal rats, AVP probably reduces water losses through extrarenal sites, probably the lungs.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Diabetes Insípido/urina , Morfolinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Masculino , Ratos , Vasopressinas/metabolismo , Vasopressinas/farmacologia , Água/metabolismoRESUMO
OBJECTIVE: To study the relationship between the sensitivity to sodium content of the diet in terms of development of hypertension and the regulation of the expression of type 1 angiotensin II receptor subtypes by such a diet. METHODS: The expression of angiotensin II receptor subtype (AT1A and AT1B) mRNAs was studied by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the four zones of the kidneys of Sabra rats, sensitive or resistant to DOCA salt-induced hypertension (SBH/y and SBN/y, respectively). Rats were fed a high (8%) or normal (0.4%) NaCl diet. As vasopressin is known to be elevated in SBH/y rats and to be involved in DOCA-salt hypertension, we studied an additional group of SBH/y rats, fed a high sodium diet, enriched in water. RESULTS: With the absence of DOCA, SBH/y rats did not develop hypertension. The high sodium diet induced a greater fall in the plasma renin activity in the SBH/y (-95%) than in the SBN/y (-63%). In the cortex (C) and inner stripe (IS), the high sodium diet decreased AT1A and AT1B mRNAs in SBH/y and SBN/y, with a higher magnitude for SBH/y, than for SBN/y (C, -28 versus -20%; IS, -42 versus -20%). The addition of water to the high sodium diet lessened the effect of sodium in the C and IS, although the plasma renin activity (PRA) was not altered. CONCLUSION: A high sodium diet significantly decreases both AT1A and AT1B gene expression in two specific zones of the rat kidney containing the target cells of angiotensin II (C and IS). This down-regulation is organ-specific since it was observed in the kidney and adrenals, but not in the liver. Finally, SBH/y and SBN/y rats differ in the basal level of AT1 mRNA expression in the IS, and in the ability to modulate AT1 mRNA level under sodium intake.
Assuntos
Rim/metabolismo , RNA Mensageiro/biossíntese , Receptores de Angiotensina/biossíntese , Sódio/farmacologia , Aldosterona/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Dieta , Hematócrito , Rim/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Circulação Renal/efeitos dos fármacos , Renina/sangue , Sódio/sangue , Urodinâmica/efeitos dos fármacosRESUMO
We have previously shown that a chronic reduction in plasma vasopressin level slowed the progression of chronic renal failure (CRF) in Sprague Dawley rats. The aim of the present study was to determine the respective contribution of pressor (V1) and antidiuretic (V2) effects of vasopressin on progression. Male homozygous Brattleboro rats with hereditary central diabetes insipidus were submitted to 5/6 nephrectomy. They were divided into three groups, two of which received chronic i.p. infusion of AVP (V1 + V2 effects) or dDAVP (V2 effects). The third group served as control (CONT). The doses of AVP and dDAVP were chosen so as to produce urine osmolality similar to that observed in 5/6 Nx Sprague Dawley rats. All rats ate the same amount of food and drank water ad libitum. Renal function was studied for 13 weeks. All three groups showed a marked hypertension. Rats infused with dDAVP, but not those infused with AVP, had a higher creatininemia, anemia and urinary protein excretion than CONT rats. In the dDAVP but not the AVP group, fractional excretion of urea was markedly decreased and plasma urea concentration rose much more than that of creatinine. These results show that V2 but not V1 effects play a major role in the deleterious influence of vasopressin on progression, at least in Brattleboro rats. The more severe progression seen in dDAVP rats could indirectly result from the V2-mediated effects on the collecting duct resulting in a decreased efficiency of urea excretion, an increased intrarenal urea recycling, and a rise in plasma urea concentration. Both the toxic effects of urea and the recently demonstrated V2-mediated increase in glomerular hemodynamics might be involved in the deleterious influence of V2 agonism.
Assuntos
Falência Renal Crônica/fisiopatologia , Rim/fisiopatologia , Vasopressinas/fisiologia , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Diabetes Insípido/genética , Modelos Animais de Doenças , Progressão da Doença , Rim/efeitos dos fármacos , Rim/patologia , Rim/cirurgia , Falência Renal Crônica/patologia , Masculino , Proteinúria/fisiopatologia , Ratos , Ratos Brattleboro , Ratos Sprague-Dawley , Uremia/fisiopatologia , Vasopressinas/deficiência , Vasopressinas/genéticaRESUMO
Diabetic nephropathy represents a major complication of diabetes mellitus (DM), and the origin of this complication is poorly understood. Vasopressin (VP), which is elevated in type I and type II DM, has been shown to increase glomerular filtration rate in normal rats and to contribute to progression of chronic renal failure in 5/6 nephrectomized rats. The present study was thus designed to evaluate whether VP contributes to the renal disorders of DM. Renal function was compared in Brattleboro rats with diabetes insipidus (DI) lacking VP and in normal Long-Evans (LE) rats, with or without streptozotocin-induced DM. Blood and urine were collected after 2 and 4 weeks of DM, and creatinine clearance, urinary glucose and albumin excretion, and kidney weight were measured. Plasma glucose increased 3-fold in DM rats of both strains, but glucose excretion was approximately 40% lower in DI-DM than in LE-DM, suggesting less intense metabolic disorders. Creatinine clearance increased significantly in LE-DM (P < 0.01) but failed to increase in DI-DM. Urinary albumin excretion more than doubled in LE-DM but rose by only 34% in DI-DM rats (P < 0.05). Kidney hypertrophy was also less intense in DI-DM than in LE-DM (P < 0.001). These results suggest that VP plays a critical role in diabetic hyperfiltration and albuminuria induced by DM. This hormone thus seems to be an additional risk factor for diabetic nephropathy and, thus, a potential target for prevention and/or therapeutic intervention.
Assuntos
Albuminúria , Diabetes Insípido/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Taxa de Filtração Glomerular , Falência Renal Crônica/fisiopatologia , Rim/fisiopatologia , Vasopressinas/fisiologia , Animais , Creatinina/metabolismo , Diabetes Insípido/genética , Glicosúria , Hipertrofia , Rim/patologia , Masculino , Nefrectomia , Tamanho do Órgão , Ratos , Ratos Brattleboro , Ratos Long-Evans , Vasopressinas/deficiência , Vasopressinas/genéticaAssuntos
Diurese , Rim/fisiologia , Natriurese , Equilíbrio Hidroeletrolítico/fisiologia , Água Corporal/metabolismo , Ingestão de Líquidos , Humanos , Hipertensão/fisiopatologia , Hipertensão/urina , Modelos Biológicos , Concentração Osmolar , Sódio/metabolismo , Sódio na Dieta/farmacocinética , Urina/química , Desequilíbrio Hidroeletrolítico/etiologia , Desequilíbrio Hidroeletrolítico/fisiopatologia , Desequilíbrio Hidroeletrolítico/urinaRESUMO
The localization of two type 1 angiotensin II receptor subtype mRNA, AT1A and AT1B, was determined by reverse transcription-PCR on microdissected glomeruli and nephron segments. The coupling sensitivity of these two receptor subtypes was evaluated by measuring variations in intracellular calcium ([Ca2+]i) elicited by angiotensin II (Ang II) in structures expressing either AT1A or AT1B mRNA, using Fura-2 fluorescence. The highest expression of AT1 mRNA was found in glomerulus, proximal tubule, and thick ascending limb. In glomerulus, AT1A and AT1B mRNA were similarly expressed, whereas in all nephron segments AT1A mRNA expression was dominant (approximately 84%). The increase in [Ca2+]i elicited by 10(-7) mol/L Ang II was highest in proximal segments (delta [Ca2+]i is approximately equivalent to 300 to 400 nmol/L) and thick ascending limb (delta [Ca2+]i is approximately equivalent to 200 nmol/L). In glomerulus and collecting duct, the response was lower (delta < 100 nmol/L). The median effective concentrations for Ang II were of the same order of magnitude in glomerulus (12.2 nmol/L), in which both AT1A and AT1B are expressed, and in cortical thick ascending limb (10.3 nmol/ L), in which AT1A is almost exclusively expressed. The Ang II-induced calcium responses were totally abolished by the AT1 receptor antagonist losartan (1 mumol/L) but not by the AT2 antagonist PD 123319 (1 mumol/L). In the absence of external Ca2+, the peak phase of the response induced by 10(-7) mol/L Ang II was reduced and shortened, suggesting that a part of the [Ca2+]i increase originated from the mobilization of the intracellular Ca2+ pool. In conclusion, these results demonstrate that in the rat kidney: (1) AT1A is the predominant AT1 receptor subtype expressed in the nephron segments, (2) glomerulus is the only structure with a relatively high AT1B mRNA content, and (3) AT1A and AT1B receptor subtypes do not differ in their efficiency for the activation of calcium second-messenger system.
Assuntos
Canais de Cálcio/metabolismo , Néfrons/metabolismo , RNA Mensageiro/análise , Receptores de Angiotensina/análise , Análise de Variância , Angiotensina II/administração & dosagem , Angiotensina II/fisiologia , Antagonistas de Receptores de Angiotensina , Animais , Canais de Cálcio/efeitos dos fármacos , Técnicas de Cultura , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , Néfrons/efeitos dos fármacos , Reação em Cadeia da Polimerase , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/classificaçãoRESUMO
The effects of glucagon (G) on proximal tubule reabsorption (PTR) and GFR seem to depend on a prior action of this hormone on the liver resulting in the liberation of a mediator and/or of a compound derived from amino acid metabolism. This study investigates in anesthetized rats the possible contribution of cAMP and urea, alone and in combination with a low dose of G, on phosphate excretion (known to depend mostly on PTR) and GFR. After a 60-min control period, cAMP (5 nmol/min x 100 grams of body weight [BW]) or urea (2.5 micromol/min x 100 grams BW) was infused intravenously for 200 min with or without G (1.2 ng/min x 100 grams BW, a physiological dose which, alone, does not influence PTR or GFR). cAMP increased markedly the excretion of phosphate and sodium (+303 and +221%, respectively, P < 0.01 for each) but did not alter GFR. Coinfusion of cAMP and G induced the same tubular effects but also induced a 20% rise in GFR (P < 0.05). Infusion of urea, with or without G, did not induce significant effects on PTR or GFR. After G infusion at increasing doses, the increase in fractional excretion of phosphate was correlated with a simultaneous rise in plasma cAMP concentration and reached a maximum for doubling of plasma cAMP. These results suggest that cAMP, normally released by the liver into the blood under the action of G, (a) is probably an essential hepatorenal link regulating the intensity of PTR, and (b) contributes, in conjunction with specific effects of G on the nephron, to the regulation of GFR.
Assuntos
AMP Cíclico/farmacologia , AMP Cíclico/fisiologia , Glucagon/farmacologia , Capacidade de Concentração Renal/fisiologia , Rim/fisiologia , Natriurese/fisiologia , Ureia/farmacologia , Animais , Arginina Vasopressina/farmacologia , AMP Cíclico/sangue , Masculino , Fosfatos/metabolismo , Ratos , Ratos Wistar , Fármacos Renais/farmacologia , Ureia/sangue , Água/metabolismoRESUMO
To evaluate the possible influence of chronic alterations in urine concentrating activity (CA) on renal hemodynamics, adult male Sprague-Dawley rats were submitted for 7 days to one of three different levels of CA. CA was either reduced by increasing water intake (mixing the food with a gel bringing 1.6 mL water per g food) (Low-CA), or increased by chronic intraperitoneal infusion of 1-desamino 8-D-arginine vasopressin (200 ng/day) (High-CA). Low-CA, High-CA, and control rats were housed in metabolic cages, ate the same quantity of dry food (the amount provided being slightly lower than the spontaneous intake), and had free access to drinking water. The only difference between groups thus concerned the water intake-vasopressin axis. Radiolabeled (14C)inulin was infused chronically by osmotic minipumps. Urine was collected during Days 5, 6, and 7, and blood samples were taken for determination of plasma composition (P), absolute and fractional (FE) urinary excretion, and clearance (C) of inulin, creatinine, urea, and main electrolytes. This protocol produced mean 24-h urine osmolality (Uosm) ranging from 500 to 3500 mosmol/kg H2O without inducing any disturbance in body fluids or plasma osmolality (Posm). Results show that GFR (Cinulin) was markedly and positively correlated with Uosm (r = 0.798, P < 0.001) and free water reabsorption (r = 0.819, P < 0.001). For Uosm = 2500 mosm/kg H2O, GFR was 47% higher than for Uosm = 500 mosm/kg H2O. Ccreat underestimated GFR in High-CA and overestimated it in Low-CA. FEurea was inversely related to Uosm, as expected from the increased reabsorption known to occur at low urine flows. It is tentatively proposed that the intrarenal recycling of urea, triggered by vasopressin and essential to the urinary concentrating mechanism, might influence GFR indirectly by modifying the composition of the tubular fluid at the macula densa and thus the intensity of the tubuloglomerular feedback control of GFR. Even if this mechanism remains to be confirmed, this study unequivocally demonstrates, in normal conscious rats, that the level of urinary concentrating activity has a major influence on basal GFR.
Assuntos
Diurese/fisiologia , Taxa de Filtração Glomerular/fisiologia , Vasopressinas/fisiologia , Animais , Creatinina/farmacocinética , Desamino Arginina Vasopressina/farmacologia , Ingestão de Líquidos , Capacidade de Concentração Renal/efeitos dos fármacos , Masculino , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Urina/químicaRESUMO
Urea, the major end product of protein metabolism in mammals, is the most abundant solute in the urine. Urea excretion is thought to result from filtration curtailed by some passive reabsorbtion along the nephron. This reabsorption is markedly enhanced by vasopressin and slow urinary flow rate (V), the fraction of filtered urea excreted in the urine (FEurea) falling from approximately 60% at high V to only approximately 20% at low V. In concentrated urine, normal urea excretion can be maintained only if urea filtration is elevated. This can be achieved by increasing plasma urea concentration (Purea) and/or GFR. We have shown that both parameters do increase when normal rats are submitted to chronic alterations in the water intake/vasopressin axis within the normal range of physiologic regulation. This situation is very similar to that observed after alterations in protein intake. In both cases more urea needs to be filtered, either because more of it has to be excreted, or because the efficiency of its excretion is reduced. A common mechanism is proposed to explain the rise in GFR observed in the two situations. In summary, our studies demonstrate that the antidiuretic effects of vasopressin are responsible for a significant elevation of GFR. This GFR adaptation limits the rise in Purea, a favorable effect because urea is not as harmless as usually thought. However, this hyperfiltration might have deleterious consequences in diseased kidneys.
Assuntos
Rim/fisiologia , Ureia/metabolismo , Animais , Rim/metabolismo , Proteínas/metabolismoRESUMO
We studied the localization and regulation of the two type 1 angiotensin II receptor subtypes AT(1A) and AT(1B) in different renal zones of the rat kidney by a reverse transcription-polymerase chain reaction amplification method. The yield of the reaction was quantified with an internal standard that was a 63-bp deleted mutant cRNA of the AT(1A) receptor. In kidneys of male Sprague-Dawley rats (n=4), the levels of AT(1A) and AT(1B) receptor mRNAs were highest in the inner stripe of the outer medulla, lowest in the inner medulla, and intermediate in the cortex and outer stripe of the outer medulla. Results (mean+/-SE) expressed in 10(5) molecules per microgram total RNA were for cortex outer stripe, inner stripe, and inner medulla, respectively, 171 +/- 15, 152 +/- 27, 322 +/- 10, and 73 +/- 3 for AT(1A), and 35 +/- 9, 26 +/- 1, 71 +/- 10, and 53 +/- 11 for AT(1B). In sabra rats sensitive (n=6) or resistant (n=6) to salt-induced hypertension and maintained on a normal salt diet, the percentage and level of each receptor subtype mRNA in cortex and outer stripe were similar in the two strains and comparable to those observed in Sprague-Dawley rats. However, AT(1A) of the inner stripe was significantly decreased in salt-resistant compared with salt-sensitive rats (166 +/- 28 and 318 +/- 58 10(5) molecules per microgram total RNA, respectively). These modifications were organ specific because no difference in the level of the receptor mRNAs was observed in the liver of the two Sabra rat strains, whereas a twofold increase in AT(1A) mRNA level but not in AT(1B) mRNA level was apparent in adrenal and in one renal zone, the inner stripe of the outer medulla, of hypertension-prone Sabra rats.