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1.
Am J Physiol Renal Physiol ; 318(5): F1199-F1209, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249612

RESUMO

Lithium is widely used in psychiatry as the golden standard for more than 60 yr due to its effectiveness. However, its adverse effect has been limiting its long-term use in clinic. About 40% of patients taking lithium develop nephrogenic diabetes insipidus (NDI). Lithium can also induce proliferation of collecting duct cells, leading to microcyst formation in the kidney. Lithium was considered an autophagy inducer that might contribute to the therapeutic benefit of neuropsychiatric disorders. Thus, we hypothesized that autophagy may play a role in lithium-induced kidney nephrotoxicity. To address our hypothesis, we fed mice with a lithium-containing diet with chloroquine (CQ), an autophagy inhibitor, concurrently. Lithium-treated mice presented enhanced autophagy activity in the kidney cortex and medulla. CQ treatment significantly ameliorated lithium-induced polyuria, polydipsia, natriuresis, and kaliuresis accompanied with attenuated downregulation of aquaporin-2 and Na+-K+-2Cl- cotransporter protein. The protective effect of CQ on aquaporin-2 protein abundance was confirmed in cultured cortical collecting duct cells. In addition, we found that lithium-induced proliferation of collecting duct cells was also suppressed by CQ as detected by proliferating cell nuclear antigen staining. Moreover, both phosphorylated mammalian target of rapamycin and ß-catenin expression, which have been reported to be increased by lithium and associated with cell proliferation, were reduced by CQ. Taken together, our study demonstrated that CQ protected against lithium-induced NDI and collecting duct cell proliferation possibly through inhibiting autophagy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Cloroquina/farmacologia , Diabetes Insípido Nefrogênico/prevenção & controle , Túbulos Renais Coletores/efeitos dos fármacos , Cloreto de Lítio , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular , Diabetes Insípido Nefrogênico/induzido quimicamente , Diabetes Insípido Nefrogênico/metabolismo , Diabetes Insípido Nefrogênico/patologia , Dinoprostona/urina , Modelos Animais de Doenças , Túbulos Renais Coletores/metabolismo , Túbulos Renais Coletores/patologia , Masculino , Camundongos da Linhagem 129 , Natriurese/efeitos dos fármacos , Fosforilação , Poliúria/induzido quimicamente , Poliúria/metabolismo , Poliúria/patologia , Poliúria/prevenção & controle , Membro 1 da Família 12 de Carreador de Soluto/genética , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , beta Catenina/metabolismo
2.
Clin Sci (Lond) ; 134(7): 871-884, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32202299

RESUMO

Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding ß-amino acid. ß-Amino acid substitution at the proline residue of Ang III (ß-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of ß-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of ß-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and ß-Pro7-Ang III in the presence of systemic AT1R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of ß-Pro7-Ang III. In both male and female rats, acute systemic administration of ß-Pro7-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of ß-Pro7-Ang III administered. Moreover, intra-renal administration of ß-Pro7-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT2R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of ß-Pro7-Ang III as a novel AT2R agonist and experimental tool for exploring AT2R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT2R stimulation on renal function.


Assuntos
Angiotensina III/análogos & derivados , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/agonistas , Circulação Renal/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Angiotensina III/farmacologia , Animais , Feminino , Rim/metabolismo , Masculino , Ratos Sprague-Dawley , Receptor Tipo 2 de Angiotensina/metabolismo , Fatores Sexuais , Transdução de Sinais
3.
Am J Physiol Renal Physiol ; 318(4): F888-F900, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036698

RESUMO

In the past decades, substantial effort has been devoted to the development of computational models of the cardiovascular system. Some of these models simulate blood pressure regulation in humans and include components of the circulatory, renal, and neurohormonal systems. Although such human models are intended to have clinical value in that they can be used to assess the effects and reveal mechanisms of hypertensive therapeutic treatments, rodent models would be more useful in assisting the interpretation of animal experiments. Also, despite well-known sexual dimorphism in blood pressure regulation, almost all published models are gender neutral. Given these observations, the goal of this project is to develop the first computational models of blood pressure regulation for male and female rats. The resulting sex-specific models represent the interplay among cardiovascular function, renal hemodynamics, and kidney function in the rat; they also include the actions of the renal sympathetic nerve activity and the renin-angiotensin-aldosterone system as well as physiological sex differences. We explore mechanisms responsible for blood pressure and renal autoregulation and notable sexual dimorphism. Model simulations suggest that fluid and sodium handling in the kidney of female rats, which differs significantly from males, may contribute to their observed lower salt sensitivity as compared with males. Additionally, model simulations highlight sodium handling in the kidney and renal sympathetic nerve activity sensitivity as key players in the increased resistance of females to angiotensin II-induced hypertension as compared with males.


Assuntos
Pressão Sanguínea , Simulação por Computador , Rim/irrigação sanguínea , Modelos Cardiovasculares , Artéria Renal/inervação , Circulação Renal , Sistema Nervoso Simpático/fisiologia , Angiotensina II , Animais , Modelos Animais de Doenças , Feminino , Homeostase , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Natriurese , Ratos Sprague-Dawley , Ratos Wistar , Caracteres Sexuais , Fatores Sexuais , Cloreto de Sódio na Dieta
4.
Am J Physiol Renal Physiol ; 318(4): F936-F955, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088967

RESUMO

Kidney water conservation requires a hypertonic medullary interstitium, NaCl in the outer medulla and NaCl and urea in the inner medulla, plus a vascular configuration that protects against washout. In this work, a multisolute model of the rat kidney is revisited to examine its capacity to simulate antidiuresis. The first step was to streamline model computation by parallelizing its Jacobian calculation, thus allowing finer medullary spatial resolution and more extensive examination of model parameters. It is found that outer medullary NaCl is modestly increased when transporter density in ascending Henle limbs from juxtamedullary nephrons is scaled to match the greater juxtamedullary solute flow. However, higher NaCl transport produces greater CO2 generation and, by virtue of countercurrent vascular flows, establishment of high medullary Pco2. This CO2 gradient can be mitigated by assuming that a fraction of medullary transport is powered anaerobically. Reducing vascular flows or increasing vessel permeabilities does little to further increase outer medullary solute gradients. In contrast to medullary models of others, vessels in this model have solute reflection coefficients close to zero; increasing these coefficients provides little enhancement of solute profiles but does generate high interstitial pressures, which distort tubule architecture. Increasing medullary urea delivery via entering vasa recta increases inner medullary urea, although not nearly to levels found in rats. In summary, 1) medullary Na+ and urea gradients are not captured by the model and 2) the countercurrent architecture that provides antidiuresis also produces exaggerated Pco2 profiles and is an unappreciated constraint on models of medullary function.


Assuntos
Simulação por Computador , Rim/irrigação sanguínea , Rim/metabolismo , Modelos Biológicos , Natriurese , Circulação Renal , Reabsorção Renal , Sódio/urina , Animais , Dióxido de Carbono/metabolismo , Pressão Hidrostática , Oxigênio/metabolismo , Permeabilidade , Potássio/urina , Ratos , Ureia/metabolismo
5.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R418-R427, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913682

RESUMO

Genes for the epithelial sodium channel (ENaC) subunits are expressed in a circadian manner, but whether this results in time-of-day differences in activity is not known. Recent data show that protein expression of ENaC subunits is higher in kidneys from female rats, yet females are more efficient in excreting an acute salt load. Thus, our in vivo study determined whether there is a time-of-day difference as well as a sex difference in the response to ENaC inhibition by benzamil. Our results showed that the natriuretic and diuretic responses to a single dose of benzamil were significantly greater in male compared with female rats whether given at the beginning of the inactive period [Zeitgeber time 0 (ZT0), 7 AM] or active period (ZT12, 7 PM). However, the response to benzamil was not significantly different between ZT0 and ZT12 dosing in either male or female rats. There was no difference in renal cortical α-ENaC protein abundance between ZT0 and ZT12 or males and females. Given previous reports of flow-induced stimulation of endothelin-1 (ET-1) production and sex differences in the renal endothelin system, we measured urinary ET-1 excretion to assess the effects of increased urine flow on intrarenal ET-1. ET-1 excretion was significantly increased following benzamil administration in both sexes, but this increase was significantly greater in females. These results support the hypothesis that ENaC activity is less prominent in maintaining Na+ balance in females independent of renal ET-1. Because ENaC subunit genes and protein expression vary by time of day and are greater in female rat kidneys, this suggests a clear disconnect between ENaC expression and channel activity.


Assuntos
Amilorida/análogos & derivados , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/efeitos dos fármacos , Rim/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Ciclos de Atividade , Amilorida/farmacologia , Animais , Endotelina-1/urina , Canais Epiteliais de Sódio/metabolismo , Feminino , Rim/metabolismo , Masculino , Ovariectomia , Ratos Sprague-Dawley , Eliminação Renal/efeitos dos fármacos , Fatores Sexuais , Fatores de Tempo , Urodinâmica/efeitos dos fármacos
6.
Am J Physiol Renal Physiol ; 318(2): F443-F454, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841385

RESUMO

Glucagon-like peptide-1 (GLP-1) and strategies based on this blood sugar-reducing and appetite-suppressing hormone are used to treat obesity and type 2 diabetes. However, the GLP-1 receptor (GLP-1R) is also present in the kidney, where it influences renal function. The effect of GLP-1 on the kidney varies between humans and rodents. The effect of GLP-1 on kidney function also seems to vary depending on its concentration and the physiological or pathological state of the kidney. In studies with rodents or humans, acute infusion of pharmacological doses of GLP-1 stimulates natriuresis and diuresis. However, the effect on the renal vasculature is less clear. In rodents, GLP-1 infusion increases renal plasma flow and glomerular filtration rate, suggesting renal vasodilation. In humans, only a subset of the study participants exhibits increased renal plasma flow and glomerular filtration rate. Differential status of kidney function and changes in renal vascular resistance of the preglomerular arterioles may account for the different responses of the human study participants. Because renal function in patients with type 2 diabetes is already at risk or compromised, understanding the effects of GLP-1R activation on kidney function in these patients is particularly important. This review examines the distribution of GLP-1R in the kidney and the effects elicited by GLP-1 or GLP-1R agonists. By integrating results from acute and chronic studies in healthy individuals and patients with type 2 diabetes along with those from rodent studies, we provide insight into how GLP-1R activation affects renal function and autoregulation.


Assuntos
Taxa de Filtração Glomerular , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Natriurese , Circulação Renal , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Homeostase , Humanos , Incretinas/uso terapêutico , Rim/efeitos dos fármacos , Ligantes , Natriurese/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Transdução de Sinais
7.
Physiol Rev ; 100(1): 321-356, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31793845

RESUMO

Daily dietary potassium (K+) intake may be as large as the extracellular K+ pool. To avoid acute hyperkalemia, rapid removal of K+ from the extracellular space is essential. This is achieved by translocating K+ into cells and increasing urinary K+ excretion. Emerging data now indicate that the renal thiazide-sensitive NaCl cotransporter (NCC) is critically involved in this homeostatic kaliuretic response. This suggests that the early distal convoluted tubule (DCT) is a K+ sensor that can modify sodium (Na+) delivery to downstream segments to promote or limit K+ secretion. K+ sensing is mediated by the basolateral K+ channels Kir4.1/5.1, a capacity that the DCT likely shares with other nephron segments. Thus, next to K+-induced aldosterone secretion, K+ sensing by renal epithelial cells represents a second feedback mechanism to control K+ balance. NCC's role in K+ homeostasis has both physiological and pathophysiological implications. During hypovolemia, NCC activation by the renin-angiotensin system stimulates Na+ reabsorption while preventing K+ secretion. Conversely, NCC inactivation by high dietary K+ intake maximizes kaliuresis and limits Na+ retention, despite high aldosterone levels. NCC activation by a low-K+ diet contributes to salt-sensitive hypertension. K+-induced natriuresis through NCC offers a novel explanation for the antihypertensive effects of a high-K+ diet. A possible role for K+ in chronic kidney disease is also emerging, as epidemiological data reveal associations between higher urinary K+ excretion and improved renal outcomes. This comprehensive review will embed these novel insights on NCC regulation into existing concepts of K+ homeostasis in health and disease.


Assuntos
Rim/metabolismo , Potássio/metabolismo , Cloreto de Sódio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Animais , Homeostase , Humanos , Hipertensão , Rim/fisiologia , Natriurese , Insuficiência Renal Crônica
8.
Am J Cardiol ; 124 Suppl 1: S36-S44, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31741439

RESUMO

The findings of recent clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors produce effects beyond glucose lowering and have demonstrated beneficial cardiovascular effects that have been observed across a broad range of patients with type 2 diabetes mellitus. In particular, the cardiovascular benefit results largely from substantial and early effects of SGLT2 inhibition on cardiovascular death and hospitalization for heart failure. Recent cardiovascular outcomes trials (CVOTs) have also shown that relative risk reductions in cardiovascular outcomes were observed with SGLT2 inhibition both in patients with current and prior heart failure. Since the observed reductions of cardiovascular outcomes with SGLT2 inhibitor therapy were observed much earlier than would be expected by an anti-atherosclerotic effect, these results have led to speculation about the potential underlying pathways. Suggested mechanisms include natriuresis and osmotic diuresis; reductions in inflammation, oxidative stress, and arterial stiffness; reductions in blood pressure and body weight; and possible renoprotective effects. These effects could produce cardiovascular benefits through a range of cardiac effects, including reduction in left ventricular load, attenuation of cardiac fibrosis and inflammation, and improved myocardial energy production. Other possible mechanisms include inhibition of sodium-hydrogen exchange, increases in erythropoietin levels, and reduction in myocardial ischemia or reperfusion injury. It is likely that a range of mechanisms underlie the observed cardiovascular benefits of SGLT2 inhibitors; further elucidation of these mechanisms will be answered by ongoing research.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diurese/efeitos dos fármacos , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Rigidez Vascular/efeitos dos fármacos , Doenças Cardiovasculares , Sistema Cardiovascular/efeitos dos fármacos , Eritropoetina , Humanos , Inflamação , Rim/efeitos dos fármacos , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Natriurese/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio
9.
Int J Clin Pharmacol Ther ; 57(12): 603-606, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31657712

RESUMO

Residual renal function and diuresis preservation are associated with improved volume control and lower mortality in peritoneal dialysis (PD). Loop diuretics are used to maintain diuresis, although their optimal dosage remains unclear. This study aimed to compare the pharmacodynamics of a 250-mg and a 500-mg dose of oral furosemide in PD patients. 12 patients with a diuresis > 100 mL per day were randomized in a crossover pattern to successively receive an oral dose of 250 mg and 500 mg of furosemide. Twelve-hour natriuresis and diuresis were measured before and after each furosemide dose. Fractional excretion of sodium (FENa) and absolute sodium excretion increased after each dose, although these rises were not statistically significantly different (5.8% (250 mg) vs. 6.9% (500 mg), p = 0.57 for FENa and 42.6 mmol/12h (250 mg) vs. 70.8 mmol/12h (500 mg), p = 0.07 for absolute sodium excretion). Urinary volume was significantly increased after the 500-mg dose, whilst the difference did not reach statistical significance after the 250-mg dose. Furthermore, the higher dose was associated with a greater increase in diuresis than the lower dose (226 mL (250 mg) vs. 522 mL (500 mg), p = 0.04). Furosemide could be used at oral single doses reaching 500 mg in PD patients requiring greater volume control.


Assuntos
Diuréticos/administração & dosagem , Diuréticos/farmacocinética , Furosemida/administração & dosagem , Furosemida/farmacocinética , Diálise Peritoneal , Diurese , Humanos , Natriurese
10.
J Pharm Pharmacol ; 71(12): 1832-1838, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31588559

RESUMO

OBJECTIVES: This study aimed to investigate the diuretic efficacy of myricetin-3-O-α-rhamnoside (myricitrin), a common naturally occurring plant-derived flavonoid, obtained from Marlierea eugeniopsoides (D.Legrand & Kausel) D.Legrand leaves in rats. METHODS: For that, female Wistar rats were treated by oral route with the different treatments and kept in metaboloic cages for 8-h or 24-h experiment. The volume and urinary parameters were measured at the end of the period and compared between groups. KEY FINDINGS: When orally given to rats and compared to the vehicle-treated group, myricitrin (0.3 and 1 mg/kg) was able to stimulate rat diuresis, natriuresis and kaliuresis. The combination myricitrin plus hydrochlorothiazide, but not plus furosemide or amiloride, potentiated the urinary volume when compared to the effects of drugs alone. Besides, the 8-h renal effects of myricitrin were prevented in the presence of a cyclooxygenase inhibitor and a muscarinic receptor antagonist. However, all groups treated with myricitrin showed a significant reduction in Cl- excretion. In addition, a reduction in the urinary excretion of Cl- and HCO 3 - was detected on 24-h analysis, a result that showed to be associated with an increase of these anions in the blood samples from the myricitrin-treated group. Despite these alterations, no changes in urinary or blood pH were detected. CONCLUSIONS: Taking together, although the results of this study point to the diuretic potential of myricitrin, the reduction in urinary Cl- and HCO 3 - excretion should be considered in future approaches, as well as for therapeutic applicability.


Assuntos
Diuréticos/farmacologia , Flavonoides/farmacologia , Myrtaceae/química , Animais , Diurese/efeitos dos fármacos , Diuréticos/administração & dosagem , Diuréticos/isolamento & purificação , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Flavonoides/administração & dosagem , Flavonoides/isolamento & purificação , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/farmacologia , Natriurese/efeitos dos fármacos , Ratos , Ratos Wistar
11.
Am J Physiol Renal Physiol ; 317(6): F1656-F1668, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31657247

RESUMO

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg-1·min-1 is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2Cl- cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg-1·min-1 raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-Cl- cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.


Assuntos
Angiotensina II/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Néfrons/metabolismo , Sódio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Simulação por Computador , Creatinina/metabolismo , Canais Epiteliais de Sódio , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Lítio/urina , Masculino , Natriurese/efeitos dos fármacos , Potássio/metabolismo , Ratos , Sódio/urina , Trocador 3 de Sódio-Hidrogênio/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/metabolismo
12.
Am J Physiol Heart Circ Physiol ; 317(5): H958-H968, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31490733

RESUMO

Previously we have shown that increased expression of renal epithelial sodium channels (ENaC) may contribute to the renal sodium and water retention observed during chronic heart failure (CHF). The goal of this study was to examine whether renal denervation (RDN) changed the expressions of renal sodium transporters ENaC, sodium-hydrogen exchanger-3 proteins (NHE3), and water channel aquaporin 2 (AQP2) in rats with CHF. CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, surgical bilateral RDN was performed. The expression of ENaC, NHE3, and AQP2 in both renal cortex and medulla were measured. As a functional test for ENaC activation, diuretic and natriuretic responses to ENaC inhibitor benzamil were monitored in four groups of rats (Sham, Sham+RDN, CHF, CHF+RDN). Western blot analysis indicated that RDN (1 wk later) significantly reduced protein levels of α-ENaC, ß-ENaC, γ-ENaC, and AQP2 in the renal cortex of CHF rats. RDN had no significant effects on the protein expression of kidney NHE3 in both Sham and CHF rats. Immunofluorescence studies of kidney sections confirmed the reduced signaling of ENaC and AQP2 in the CHF+RDN rats compared with the CHF rats. There were increases in diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. RDN reduced the diuretic and natriuretic responses to benzamil in CHF rats. These findings suggest a critical role for renal nerves in the enhanced expression of ENaC and AQP2 and subsequent pathophysiology of renal sodium and water retention associated with CHF.NEW & NOTEWORTHY This is the first study to show in a comprehensive way that renal denervation initiated after a period of chronic heart failure reduces the expression of epithelial sodium channels and aquaporin 2 leading to reduced epithelial sodium channel function and sodium retention.


Assuntos
Aquaporina 2/metabolismo , Denervação Autônoma , Canais Epiteliais de Sódio/metabolismo , Insuficiência Cardíaca/metabolismo , Rim/inervação , Rim/metabolismo , Natriurese , Eliminação Renal , Sódio/urina , Amilorida/análogos & derivados , Amilorida/farmacologia , Animais , Aquaporina 2/genética , Doença Crônica , Modelos Animais de Doenças , Diuréticos/farmacologia , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/efeitos dos fármacos , Canais Epiteliais de Sódio/genética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/urina , Rim/efeitos dos fármacos , Masculino , Natriurese/efeitos dos fármacos , Ratos Sprague-Dawley , Eliminação Renal/efeitos dos fármacos
13.
Pol Merkur Lekarski ; 47(278): 72-75, 2019 Aug 30.
Artigo em Polonês | MEDLINE | ID: mdl-31473757

RESUMO

INTRODUCTION: Cerebral salt wasting syndrome (CSWS), characterized by natriuresis, polyuria, and hypovolemia, is a rare complication of central nervous system injury or disease. A CASE STUDY: 12-year-old girl was admitted with second attack of nephrotic syndrome (NS). On admission she presents with edema, blood pressure 110/60 mm Hg, proteinuria 145 mg/kg/24h, hypoalbuminemia (1.7 g/dL), GFR 94.4 mL/min/1.73m2, sodium 133 mmol/L. On 5th day the patient developed thrombosis of right subclavian and axillary vein and was treated with recombinant tissue plasminogen activator (0.3 mg/kg/h i.v.). 45 minutes after onset of the infusion severe headache appeared. Computed tomography revealed subarachnoid hemorrhage in a region of left occipital lobe and posterior 1/3 part of sickle of the brain. Control ultrasonography examination revealed resolution of the thrombus. No deficits were found on neurologic examination. Proteinuria subsided on 11th day of hospitalization. After the hemorrhage hypovolemia, hypotension (80/40 - 100/60 mm Hg, heart rate 100/min), polyuria, and pathologic natriuresis (up to 13.0 mmol/kg/24h) were observed. Cerebral salt wasting syndrome was recognized. The girl was supplemented with oral and intravenous sodium (up to 10 mmol/ kg/24h). In following days gradual decrease of diuresis and urinary sodium loss was observed. The patient was discharged home after 41 days with normal diuresis (1.5l/24h) and natriuresis (1.44 mmol/kg/24h). CONCLUSIONS: Treatment of thromboembolic complications in children with NS poses a risk of central nervous system bleeding. Serum sodium concentration and diuresis must be strictly monitored in patients with central nervous system lesion, especially in the course of nephrotic syndrome.


Assuntos
Hiponatremia , Síndrome Nefrótica , Hemorragia Subaracnóidea , Criança , Feminino , Humanos , Hiponatremia/complicações , Natriurese , Síndrome Nefrótica/complicações , Hemorragia Subaracnóidea/complicações , Síndrome , Ativador de Plasminogênio Tecidual , Equilíbrio Hidroeletrolítico
14.
Am J Physiol Renal Physiol ; 317(4): F949-F956, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31411069

RESUMO

The role of dopamine D1-like receptors (DR) in the regulation of renal Na+ transporters, natriuresis, and blood pressure is well established. However, the involvement of the angiotensin 1-7 (ANG 1-7)-Mas receptor in the regulation of Na+ balance and blood pressure is not clear. The present study aimed to investigate the hypothesis that ANG 1-7 can regulate Na+ homeostasis by modulating the renal dopamine system. Sprague-Dawley rats were infused with saline alone (vehicle) or saline with ANG 1-7, ANG 1-7 antagonist A-779, DR agonist SKF38393, and antagonist SCH23390. Infusion of ANG 1-7 caused significant natriuresis and diuresis compared with saline alone. Both natriuresis and diuresis were blocked by A-779 and SCH23390. SKF38393 caused a significant, SCH23390-sensitive natriuresis and diuresis, and A-779 had no effect on the SKF38393 response. Concomitant infusion of ANG 1-7 and SKF38393 did not show a cumulative effect compared with either agonist alone. Treatment of renal proximal tubules with ANG 1-7 or SKF38393 caused a significant decrease in Na+-K+-ATPase and Na+/H+ exchanger isoform 3 activity. While SCH23390 blocked both ANG 1-7- and SKF38393-induced inhibition, the DR response was not sensitive to A-779. Additionally, ANG 1-7 activated PKG, enhanced tyrosine hydroxylase activity via Ser40 phosphorylation, and increased renal dopamine production. These data suggest that ANG 1-7, via PKG, enhances tyrosine hydroxylase activity, which increases renal dopamine production and activation of DR and subsequent natriuresis. This study provides evidence for a unidirectional functional interaction between two G protein-coupled receptors to regulate renal Na+ transporters and induce natriuresis.


Assuntos
Angiotensina I/farmacologia , Rim/metabolismo , Fragmentos de Peptídeos/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sódio/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Angiotensina I/antagonistas & inibidores , Animais , Benzazepinas/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Diurese/efeitos dos fármacos , Dopamina/biossíntese , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Natriurese/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo
16.
Circulation ; 140(6): 443-445, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31381418
18.
Am J Physiol Renal Physiol ; 317(4): F1010-F1021, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390233

RESUMO

Glucagon-like peptide-1 (GLP-1), an incretin hormone, has diuretic and natriuretic effects. The present study was designed to explore the possible underlying mechanisms for the diuretic and natriuretic effects of GLP-1 via renal nerves in rats. Immunohistochemistry revealed that GLP-1 receptors were avidly expressed in the pelvic wall, the wall being adjacent to afferent renal nerves immunoreactive to calcitonin gene-related peptide, which is the dominant neurotransmitter for renal afferents. GLP-1 (3 µM) infused into the left renal pelvis increased ipsilateral afferent renal nerve activity (110.0 ± 15.6% of basal value). Intravenous infusion of GLP-1 (1 µg·kg-1·min-1) for 30 min increased renal sympathetic nerve activity (RSNA). After the distal end of the renal nerve was cut to eliminate the afferent signal, the increase in efferent renal nerve activity during intravenous infusion of GLP-1 was diminished compared with the increase in total RSNA (17.0 ± 9.0% vs. 68.1 ± 20.0% of the basal value). Diuretic and natriuretic responses to intravenous infusion of GLP-1 were enhanced by total renal denervation (T-RDN) with acute surgical cutting of the renal nerves. Selective afferent renal nerve denervation (A-RDN) was performed by bilateral perivascular application of capsaicin on the renal nerves. Similar to T-RDN, A-RDN enhanced diuretic and natriuretic responses to GLP-1. Urine flow and Na+ excretion responses to GLP-1 were not significantly different between T-RDN and A-RDN groups. These results indicate that the diuretic and natriuretic effects of GLP-1 are partly governed via activation of afferent renal nerves by GLP-1 acting on sensory nerve fibers within the pelvis of the kidney.


Assuntos
Vias Aferentes/efeitos dos fármacos , Diurese/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Rim/efeitos dos fármacos , Rim/inervação , Natriurese/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Denervação , Peptídeo 1 Semelhante ao Glucagon/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/imunologia , Células HEK293 , Humanos , Pelve Renal/efeitos dos fármacos , Pelve Renal/inervação , Masculino , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos , Sódio/urina , Sistema Nervoso Simpático/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos
19.
PLoS One ; 14(7): e0219205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31269062

RESUMO

In the rat, oxytocin (OT) produces dose-dependent diuretic and natriuretic responses. Post-translational enzymatic conversion of the OT biosynthetic precursor forms both mature and C-terminally extended peptides. The plasma concentrations of these C-terminally extended peptides (OT-G; OT-GK and OT-GKR) are elevated in newborns and pregnant rats. Intravenous injection of OT-GKR to rats inhibits diuresis, whereas injection of amidated OT stimulates diuresis. Since OT and OT-GKR show different effects on the urine flow, we investigated whether OT-GKR modulates renal action by inhibition of the arginine-vasopressin (AVP) receptor V2 (V2R), the receptor involved in renal water reabsorption. Experiments were carried out in the 8-week-old Wistar rats receiving intravenous (iv) injections of vehicle, OT, OT-GKR or OT+OT-GKR combination. OT (10 µmol/kg) increased urine outflow by 40% (P<0.01) and sodium excretion by 47% (P<0.01). Treatment with OT-GKR (10 µmol/kg) decreased diuresis by 50% (P<0.001), decreased sodium excretion by 50% (P<0.05) and lowered potassium by 42% (P<0.05). OT antagonist (OTA) reduced diuresis and natriuresis exerted by OT, whereas the anti-diuretic effect of OT-GKR was unaffected by OTA. The treatment with V2R antagonist (V2A) in the presence and absence of OT induced diuresis, sodium and potassium outflow. V2A in the presence of OT-GKR only partially increased diuresis and natriuresis. Autoradiography and molecular docking analysis showed potent binding of OT-GKR to V2R. Finally, the release of cAMP from CHO cells overexpressing V2 receptor was induced by low concentration of AVP (EC50:4.2e-011), at higher concentrations of OT (EC50:3.2e-010) and by the highest concentrations of OT-GKR (EC50:1.1e-006). OT-GKR potentiated cAMP release when combined with AVP, but blocked cAMP release when combined with OT. These results suggest that OT-GKR by competing for the OT renal receptor (OTR) and binding to V2R in the kidney, induces anti-diuretic, anti-natriuretic, and anti-kaliuretic effects.


Assuntos
Diurese , Natriurese , Ocitocina/metabolismo , Animais , Autorradiografia , Ligação Competitiva , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Eletrólitos/metabolismo , Humanos , Rim/metabolismo , Simulação de Acoplamento Molecular , Peptídeos/metabolismo , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismo , Micção , Vasopressinas/metabolismo
20.
Cardiovasc Diabetol ; 18(1): 88, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288813

RESUMO

BACKGROUND: Hypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship. METHODS: We included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes. RESULTS: During median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP. CONCLUSIONS: The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.


Assuntos
Pressão Sanguínea , Isquemia Encefálica/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Hipertensão/epidemiologia , Hemorragias Intracranianas/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Adulto , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/urina , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/urina , Feminino , Finlândia/epidemiologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipertensão/urina , Incidência , Hemorragias Intracranianas/fisiopatologia , Hemorragias Intracranianas/urina , Masculino , Pessoa de Meia-Idade , Natriurese , Potássio/urina , Prognóstico , Eliminação Renal , Medição de Risco , Fatores de Risco , Sódio/urina , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/urina , Fatores de Tempo
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