RESUMO
BACKGROUND: Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the ß-splice variant of nitric oxide synthase 1 (NOS1ß) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1ß in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease. METHODS: We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1ß/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice. RESULTS: Macula densa NOS1ß was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1ß, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1ß expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies. CONCLUSIONS: Macula densa NOS1ß plays a critical role in the control of renal hemodynamics and BP during pregnancy.
Assuntos
Pressão Arterial , Hipertensão Induzida pela Gravidez/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais Distais/fisiopatologia , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Chlorocebus aethiops , Retroalimentação Fisiológica , Feminino , Taxa de Filtração Glomerular , Hipertensão Induzida pela Gravidez/metabolismo , Hipertensão Induzida pela Gravidez/patologia , Isoenzimas , Túbulos Renais Distais/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/genética , Gravidez , Circulação Renal , Regulação para Cima , Útero/irrigação sanguíneaRESUMO
The genetic disease Gitelman syndrome, knockout mice, and pharmacological blockade with thiazide diuretics have revealed that reduced activity of the NaCl cotransporter (NCC) promotes renal Mg2+ wasting. NCC is expressed along the distal convoluted tubule (DCT), and its activity determines Mg2+ entry into DCT cells through transient receptor potential channel subfamily M member 6 (TRPM6). Several other genetic forms of hypomagnesemia lower the drive for Mg2+ entry by inhibiting activity of basolateral Na+-K+-ATPase, and reduced NCC activity may do the same. Lower intracellular Mg2+ may promote further Mg2+ loss by directly decreasing activity of Na+-K+-ATPase. Lower intracellular Mg2+ may also lower Na+-K+-ATPase indirectly by downregulating NCC. Lower NCC activity also induces atrophy of DCT cells, decreasing the available number of TRPM6 channels. Conversely, a mouse model with increased NCC activity was recently shown to display normal Mg2+ handling. Moreover, recent studies have identified calcineurin and uromodulin (UMOD) as regulators of both NCC and Mg2+ handling by the DCT. Calcineurin inhibitors paradoxically cause hypomagnesemia in a state of NCC activation, but this may be related to direct effects on TRPM6 gene expression. In Umod-/- mice, the cause of hypomagnesemia may be partly due to both decreased NCC expression and lower TRPM6 expression on the cell surface. This mini-review discusses these new findings and the possible role of altered Na+ flux through NCC and ultimately Na+-K+-ATPase in Mg2+ reabsorption by the DCT.
Assuntos
Síndrome de Gitelman/metabolismo , Túbulos Renais Distais/metabolismo , Magnésio/metabolismo , Eliminação Renal , Reabsorção Renal , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Animais , Calcineurina/metabolismo , Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatologia , Humanos , Túbulos Renais Distais/fisiopatologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/genética , Canais de Cátion TRPM/metabolismo , Uromodulina/metabolismoAssuntos
Insuficiência Renal Crônica/genética , Uromodulina/genética , Uromodulina/metabolismo , Uromodulina/urina , Injúria Renal Aguda/metabolismo , Animais , Biomarcadores/sangue , Pressão Sanguínea , Doenças Cardiovasculares/sangue , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Túbulos Renais Distais/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Cloreto de Sódio/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Infecções Urinárias/urina , Uromodulina/sangueRESUMO
Background Angiotensin II stimulates epithelial Na+ channel (ENaC) by aldosterone-independent mechanism. We now test the effect of angiotensin II on ENaC in the distal convoluted tubule (DCT) and cortical collecting duct (CCD) of wild-type (WT) and kidney-specific mineralocorticoid receptor knockout mice (KS-MR-KO). Methods and Results We used electrophysiological, immunoblotting and renal-clearance methods to examine the effect of angiotensin II on ENaC in KS-MR-KO and wild-type mice. High K+ intake stimulated ENaC in the late DCT/early connecting tubule (DCT2/CNT) and in the CCD whereas low sodium intake stimulated ENaC in the CCD but not in the DCT2/CNT. The deletion of MR abolished the stimulatory effect of high K+ and low sodium intake on ENaC, partially inhibited ENaC in DCT2/CNT but almost abolished ENaC activity in the CCD. Application of losartan inhibited ENaC only in DCT2/CNT of both wild-type and KS-MR-KO mice but not in the CCD. Angiotensin II infusion for 3 days has a larger stimulatory effect on ENaC in the DCT2/CNT than in the CCD. Three lines of evidence indicate that angiotensin II can stimulate ENaC by MR-independent mechanism: (1) angiotensin II perfusion augmented ENaC expression in KS-MR-KO mice; (2) angiotensin II stimulated ENaC in the DCT2/CNT but to a lesser degree in the CCD in KS-MR-KO mice; (3) angiotensin II infusion augmented benzamil-induced natriuresis, increased the renal K+ excretion and corrected hyperkalemia of KS-MR-KO mice. Conclusions Angiotensin II-induced stimulation of ENaC occurs mainly in the DCT2/CNT and to a lesser degree in the CCD and MR plays a dominant role in determining ENaC activity in the CCD but to a lesser degree in the DCT2/CNT.
Assuntos
Angiotensina II/farmacologia , Canais Epiteliais de Sódio/metabolismo , Túbulos Renais Coletores/efeitos dos fármacos , Túbulos Renais Distais/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/agonistas , Receptores de Mineralocorticoides/deficiência , Animais , Hiperpotassemia/tratamento farmacológico , Hiperpotassemia/genética , Hiperpotassemia/metabolismo , Hiperpotassemia/fisiopatologia , Túbulos Renais Coletores/metabolismo , Túbulos Renais Coletores/fisiopatologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/fisiopatologia , Potenciais da Membrana , Camundongos Knockout , Natriurese/efeitos dos fármacos , Potássio/urina , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Mineralocorticoides/genética , Eliminação Renal/efeitos dos fármacosRESUMO
Owing to its rarity and severe nature, the treatment for generalized pseudohypoaldosteronism type 1 (PHA1), a genetic disorder in the epithelial sodium channel (ENaC), is exclusively experience-based. In particular, the usefulness of dietary potassium restriction in PHA1 remains unclear with the absence of theoretical background to elucidate its utility. First, we demonstrated the effect of potassium restriction in a 13-month-old patient with ENaC γ-subunit gene mutations via a retrospective chart review; reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity. The serum potassium level decreased from 5.6 to 4.5 mEq/L. Next, we attempted to elucidate the pathophysiological basis of the usefulness of potassium restriction, leveraged by the increased knowledge regarding the roles of with-no-lysine kinases (WNKs) in the distal nephron. When potassium is restricted, the WNK signal will turn "on" in the distal nephron via reduction in the intracellular chloride level. Consequently, the sodium reabsorption from the Na+Cl- cotransporter (NCC) in the distal convoluted tubule and possibly from pendrin in the ß-intercalated cell will increase. Thus, potassium restriction causes NCC and pendrin to compensate for the non-functional ENaC in the collecting duct. In conclusion, dietary potassium restriction is one of the indispensable treatments for generalized PHA1.
Assuntos
Dietoterapia/efeitos adversos , Canais Epiteliais de Sódio/genética , Néfrons/metabolismo , Pseudo-Hipoaldosteronismo/dietoterapia , Sódio/urina , Dietoterapia/métodos , Humanos , Lactente , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/fisiopatologia , Masculino , Mutação , Néfrons/fisiopatologia , Potássio/sangue , Potássio na Dieta/administração & dosagem , Potássio na Dieta/provisão & distribuição , Proteínas Serina-Treonina Quinases/genética , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/fisiopatologia , Estudos Retrospectivos , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Transportadores de Sulfato/genética , Resultado do TratamentoRESUMO
Treatment of multi-drug resistant (MDR) tuberculosis (TB) includes aminoglycosides and ethionamide. A 16-year-old girl presented with sudden onset of paralysis, dyselectrolytemia mimicking Gitelman syndrome, and ethionamide-induced hypothyroidism. Monitoring electrolytes during MDR-TB treatment is recommended to prevent life-threatening complications.
Assuntos
Aminoglicosídeos/administração & dosagem , Etionamida/administração & dosagem , Síndrome de Gitelman/diagnóstico , Túbulos Renais Distais , Tuberculose Resistente a Múltiplos Medicamentos , Desequilíbrio Hidroeletrolítico , Adolescente , Antituberculosos/administração & dosagem , Diagnóstico Diferencial , Feminino , Humanos , Túbulos Renais Distais/patologia , Túbulos Renais Distais/fisiopatologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Paralisia/diagnóstico , Paralisia/etiologia , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/sangue , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/fisiopatologia , Desequilíbrio Hidroeletrolítico/diagnóstico , Desequilíbrio Hidroeletrolítico/etiologia , Desequilíbrio Hidroeletrolítico/prevenção & controleRESUMO
BACKGROUND: Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)-dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR. METHODS: We used microperfusion, micropuncture, and renal clearance of FITC-inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa-specific NOS1 knockout mice. RESULTS: Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa-specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR. CONCLUSIONS: We identified a novel mechanism of acute hyperglycemia-induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.
Assuntos
Glucose/metabolismo , Hiperglicemia/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais Distais/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo , Animais , Retroalimentação Fisiológica , Taxa de Filtração Glomerular , Glucosídeos/farmacologia , Humanos , Inulina/metabolismo , Glomérulos Renais/metabolismo , Túbulos Renais Distais/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo I/genética , Fosforilação , Pirazóis/farmacologia , Transdução de Sinais , Transportador 1 de Glucose-Sódio/antagonistas & inibidoresRESUMO
Renal salt handling has a profound effect on body fluid and blood pressure (BP) maintenance as exemplified by the use of diuretic medications to treat states of volume expansion or hypertension. It has recently been proposed that a low potassium (K+) intake turns on a "renal K+ switch" which increases sodium (Na+) and chloride (Cl-) reabsorption, causing salt-retention, and in susceptible individuals, this causes hypertension. A signaling network, involving with-no-lysine (WNK) kinases, underpins the switch activity to coordinate aldosterone's two essential actions (K+ secretion and Na+ retention). A dysfunctional WNK kinase network drives excessive and inappropriate Na+, Cl- and urinary K+ retention in familial hyperkalemic hypertension (FHHt, also known as Gordon's syndrome). Mutations in genes encoding WNK1 and WNK4 or components of an ubiquitin ligase complex, cullin3, and kelch-like family member 3 (KLHL3), cause FHHt by upregulating the thiazide-sensitive sodium chloride cotransporter (NCC). Inhibition of NCC with thiazide diuretics corrects hypertension and hyperkalaemia in FHHt. These observations highlight the critical role of the NCC in the regulation of Na+ and K+ balance and of BP. Here we discuss the physiology of Na+ and K+ handling in the distal renal tubule with respect to BP regulation, with a focus on recent discoveries in the WNK- Ste20-related proline-alanine-rich kinase (SPAK)-NCC pathway.
Assuntos
Pressão Sanguínea , Hipertensão/enzimologia , Túbulos Renais Distais/enzimologia , Potássio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sódio/metabolismo , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Túbulos Renais Distais/fisiopatologia , Masculino , Natriurese , Reabsorção Renal , Fatores de Risco , Transdução de Sinais , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Equilíbrio HidroeletrolíticoRESUMO
Vesicoureteric reflux (VUR) is the most common congenital anomaly of the urinary tract that occurs in 30%-50% of children presenting with recurrent urinary tract infections. Long-standing untreated VUR results in renal scarring and hydronephrotic changes ultimately leading to chronic renal failure and arterial hypertension. However, it may also result in diffuse tubulopathy compromising the concentrating capacity of tubules and urinary acidification defects. Renal tubular dysfunction should be considered in all children with VUR presenting with failure to thrive, rickets, bony deformity/pain, hypokalemia, and metabolic acidosis. We report such a case of a 16-year-old male adolescent who presented with rickets, failure to gain weight and height, bony pains, and muscle weakness with a history of VUR. On investigation, he was found to have normal anion gap metabolic acidosis with hypokalemia suggestive of distal renal tubular acidosis. He responded well to oral alkali and potassium replacement therapy.
Assuntos
Acidose Tubular Renal/etiologia , Túbulos Renais Distais , Refluxo Vesicoureteral/complicações , Acidose Tubular Renal/diagnóstico por imagem , Acidose Tubular Renal/fisiopatologia , Administração Oral , Adolescente , Álcalis/administração & dosagem , Suplementos Nutricionais , Humanos , Hipopotassemia/etiologia , Túbulos Renais Distais/diagnóstico por imagem , Túbulos Renais Distais/efeitos dos fármacos , Túbulos Renais Distais/patologia , Túbulos Renais Distais/fisiopatologia , Masculino , Potássio/administração & dosagem , Bicarbonato de Sódio/administração & dosagem , Resultado do Tratamento , Ultrassonografia , Refluxo Vesicoureteral/diagnóstico , Refluxo Vesicoureteral/fisiopatologiaRESUMO
Distal renal tubular acidosis (DRTA) is defined as hyperchloremic, non-anion gap metabolic acidosis with impaired urinary acid excretion in the presence of a normal or moderately reduced glomerular filtration rate. Failure in urinary acid excretion results from reduced H+ secretion by intercalated cells in the distal nephron. This results in decreased excretion of NH4+ and other acids collectively referred as titratable acids while urine pH is typically above 5.5 in the face of systemic acidosis. The clinical phenotype in patients with DRTA is characterized by stunted growth with bone abnormalities in children as well as nephrocalcinosis and nephrolithiasis that develop as the consequence of hypercalciuria, hypocitraturia, and relatively alkaline urine. Hypokalemia is a striking finding that accounts for muscle weakness and requires continued treatment together with alkali-based therapies. This review will focus on the mechanisms responsible for impaired acid excretion and urinary potassium wastage, the clinical features, and diagnostic approaches of hypokalemic DRTA, both inherited and acquired.
Assuntos
Acidose Tubular Renal/fisiopatologia , Hipopotassemia/etiologia , ATPases Vacuolares Próton-Translocadoras/genética , Acidose Tubular Renal/complicações , Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/tratamento farmacológico , Proteína 1 de Troca de Ânion do Eritrócito/genética , Transporte Biológico , Anidrase Carbônica II/genética , Taxa de Filtração Glomerular , Humanos , Hipopotassemia/tratamento farmacológico , Hipopotassemia/urina , Túbulos Renais Distais/fisiopatologia , Mutação , Potássio/sangue , Potássio/urinaRESUMO
Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal HCO3- absorption or new renal HCO3- generation; (3) changes in renal NH4+, Ca2+, K+, and H2O homeostasis; and (4) extrarenal manifestations that provide etiologic diagnostic clues. The focus of this review is to give a general overview of the pathogenesis of the various clinical syndromes causing RTA with a particular emphasis on type I (hypokalemic distal RTA) and type II (proximal) RTA while reviewing their pathogenesis from a physiological "bottom-up" approach. In addition, the factors involved in the generation of metabolic acidosis in both type I and II RTA are reviewed highlighting the importance of altered renal ammonia production/partitioning and new HCO3- generation. Our understanding of the underlying tubular transport and extrarenal abnormalities has significantly improved since the first recognition of RTA as a clinical entity because of significant advances in clinical acid-base chemistry, whole tubule and single-cell H+/base transport, and the molecular characterization of the various transporters and channels that are functionally affected in patients with RTA. Despite these advances, additional studies are needed to address the underlying mechanisms involved in hypokalemia, altered ammonia production/partitioning, hypercalciuria, nephrocalcinosis, cystic abnormalities, and CKD progression in these patients.
Assuntos
Desequilíbrio Ácido-Base , Acidose Tubular Renal/fisiopatologia , Amônia/metabolismo , Bicarbonatos/metabolismo , Túbulos Renais Proximais/fisiopatologia , Acidose Tubular Renal/complicações , Compostos de Amônio/urina , Animais , Transporte Biológico , Cálcio/metabolismo , Ácido Cítrico/urina , Humanos , Hipercalciúria/etiologia , Hipopotassemia/etiologia , Ácidos Cetoglutáricos/metabolismo , Túbulos Renais Distais/fisiopatologia , Simportadores de Sódio-Bicarbonato/genéticaRESUMO
Many physiological functions have a circadian rhythm, including blood pressure (BP). BP is highest during the active phase, whereas during the rest period, BP dips 10-20%. Patients that do not experience this dip at night are termed "nondippers." Nondipping hypertension is associated with increased risk of cardiovascular disease. The mechanisms underlying nondipping hypertension are not understood. Without the circadian clock gene Per1, C57BL/6J mice develop nondipping hypertension on a high-salt diet plus mineralocorticoid treatment (HS/DOCP). Our laboratory has shown that PER1 regulates expression of several genes related to sodium (Na) transport in the kidney, including epithelial Na channel (ENaC) and Na chloride cotransporter (NCC). Urinary Na excretion also demonstrates a circadian pattern with a peak during active periods. We hypothesized that PER1 contributes to circadian regulation of BP via a renal Na-handling-dependent mechanism. Na-handling genes from the distal nephron were inappropriately regulated in KO mice on HS/DOCP. Additionally, the night/day ratio of Na urinary excretion by Per1 KO mice is decreased compared with WT (4 × vs. 7×, P < 0.001, n = 6 per group). Distal nephron-specific Per1 KO mice also show an inappropriate increase in expression of Na transporter genes αENaC and NCC. These results support the hypothesis that PER1 mediates control of circadian BP rhythms via the regulation of distal nephron Na transport genes. These findings have implications for the understanding of the etiology of nondipping hypertension and the subsequent development of novel therapies for this dangerous pathophysiological condition.
Assuntos
Pressão Sanguínea , Ritmo Circadiano , Hipertensão/metabolismo , Túbulos Renais Distais/metabolismo , Natriurese , Proteínas Circadianas Period/metabolismo , Eliminação Renal , Animais , Pressão Sanguínea/genética , Ritmo Circadiano/genética , Acetato de Desoxicorticosterona , Modelos Animais de Doenças , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Predisposição Genética para Doença , Hipertensão/genética , Hipertensão/fisiopatologia , Túbulos Renais Distais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Natriurese/genética , Proteínas Circadianas Period/deficiência , Proteínas Circadianas Period/genética , Fenótipo , Eliminação Renal/genética , Cloreto de Sódio na Dieta , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Fatores de Tempo , Regulação para CimaRESUMO
Kir4.1 in the distal convoluted tubule plays a key role in sensing plasma potassium and in modulating the thiazide-sensitive sodium-chloride cotransporter (NCC). Here we tested whether dietary potassium intake modulates Kir4.1 and whether this is essential for mediating the effect of potassium diet on NCC. High potassium intake inhibited the basolateral 40 pS potassium channel (a Kir4.1/5.1 heterotetramer) in the distal convoluted tubule, decreased basolateral potassium conductance, and depolarized the distal convoluted tubule membrane in Kcnj10flox/flox mice, herein referred to as control mice. In contrast, low potassium intake activated Kir4.1, increased potassium currents, and hyperpolarized the distal convoluted tubule membrane. These effects of dietary potassium intake on the basolateral potassium conductance and membrane potential in the distal convoluted tubule were completely absent in inducible kidney-specific Kir4.1 knockout mice. Furthermore, high potassium intake decreased, whereas low potassium intake increased the abundance of NCC expression only in the control but not in kidney-specific Kir4.1 knockout mice. Renal clearance studies demonstrated that low potassium augmented, while high potassium diminished, hydrochlorothiazide-induced natriuresis in control mice. Disruption of Kir4.1 significantly increased basal urinary sodium excretion but it abolished the natriuretic effect of hydrochlorothiazide. Finally, hypokalemia and metabolic alkalosis in kidney-specific Kir4.1 knockout mice were exacerbated by potassium restriction and only partially corrected by a high-potassium diet. Thus, Kir4.1 plays an essential role in mediating the effect of dietary potassium intake on NCC activity and potassium homeostasis.
Assuntos
Túbulos Renais Distais/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Potássio na Dieta/metabolismo , Alcalose/genética , Alcalose/metabolismo , Alcalose/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Homeostase , Hidroclorotiazida/farmacologia , Hipopotassemia/genética , Hipopotassemia/metabolismo , Hipopotassemia/fisiopatologia , Túbulos Renais Distais/efeitos dos fármacos , Túbulos Renais Distais/fisiopatologia , Masculino , Potenciais da Membrana , Camundongos Knockout , Natriurese , Canais de Potássio Corretores do Fluxo de Internalização/deficiência , Canais de Potássio Corretores do Fluxo de Internalização/genética , Eliminação Renal , Sódio/urina , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Canal Kir5.1RESUMO
The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin.
Assuntos
Claudinas/deficiência , Hipercalciúria/prevenção & controle , Túbulos Renais Distais/metabolismo , Alça do Néfron/metabolismo , Deficiência de Magnésio/prevenção & controle , Animais , Cálcio/metabolismo , Claudinas/genética , Modelos Animais de Doenças , Deleção de Genes , Predisposição Genética para Doença , Hipercalciúria/genética , Hipercalciúria/metabolismo , Hipercalciúria/fisiopatologia , Túbulos Renais Distais/patologia , Túbulos Renais Distais/fisiopatologia , Alça do Néfron/patologia , Alça do Néfron/fisiopatologia , Magnésio/metabolismo , Deficiência de Magnésio/genética , Deficiência de Magnésio/metabolismo , Deficiência de Magnésio/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrocalcinose/genética , Nefrocalcinose/metabolismo , Nefrocalcinose/fisiopatologia , Nefrocalcinose/prevenção & controle , Fenótipo , Sódio/metabolismoRESUMO
The presence of renin production by the principal cells of the collecting duct has opened new perspectives for the regulation of intrarenal angiotensin II (Ang II). Angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) are present in the tubular fluid coming from the proximal tubule and collecting duct. All the components needed for Ang II formation are present along the nephron, and much is known about the mechanisms regulating renin in juxtaglomerular cells (JG); however, those in the collecting duct remain unclear. Ang II suppresses renin via protein kinase C (PKC) and calcium (Ca2+) in JG cells, but in the principal cells, Ang II increases renin synthesis and release through a pathophysiological mechanism that increases further intratubular Ang II de novo formation to enhance distal Na + reabsorption. Transgenic mice overexpressing renin in the collecting duct demonstrate the role of collecting duct renin in the development of hypertension. The story became even more interesting after the discovery of a specific receptor for renin and prorenin: the prorenin receptor ((P)RR), which enhances renin activity and fully activates prorenin. The interactions between (P)RR and prorenin/renin may further increase intratubular Ang II levels. In addition to Ang II, other mechanisms have been described in the regulation of renin in the collecting duct, including vasopressin (AVP), bradykinin (BK), and prostaglandins. Current active investigations are aimed at elucidating the mechanisms regulating renin in the distal nephron segments and understand its role in the pathogenesis of hypertension.
Assuntos
Hipertensão/metabolismo , Hipertensão/fisiopatologia , Túbulos Renais Coletores/metabolismo , Renina/metabolismo , Angiotensina II/metabolismo , Animais , Humanos , Hipertensão/etiologia , Túbulos Renais Coletores/fisiopatologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/fisiopatologia , Túbulos Renais Proximais/fisiopatologia , Renina/biossíntese , Sistema Renina-Angiotensina/fisiologiaRESUMO
Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK). Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK-deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H) that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%). These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics.
Assuntos
Cálcio/urina , Sistema Calicreína-Cinina/fisiologia , Alelos , Animais , Canais de Cálcio/deficiência , Estudos Cross-Over , Predisposição Genética para Doença , Glucuronidase/fisiologia , Humanos , Sistema Calicreína-Cinina/genética , Túbulos Renais Distais/fisiopatologia , Proteínas Klotho , Masculino , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto , Canais de Cátion TRPV/deficiência , Calicreínas Teciduais/deficiência , Calicreínas Teciduais/genéticaRESUMO
Chronic acid retention is known to promote bone dissolution. In this study, 23 % of patients with osteopenia/osteoporosis were diagnosed with abnormal distal renal tubular acidification (dRTA), a kidney dysfunction leading to chronic acid retention. Treating those patients with alkali-therapy shows improvement in bone density. To evaluate the prevalence of abnormal distal renal tubular acidification in patients with low bone mass (LBM) and the impact of additional alkali treatment on bone density in patients with concomitant LBM and dRTA,183 patients referred for metabolic evaluation of densitometrically proven low bone mass were screened for abnormal distal renal tubular acidification between 2006 and 2013. In all LBM urine pH (U-pH) was measured in the 2nd morning urines after 12 h of fasting. If U-pH was ≥5.80, LBM underwent a 1-day ammonium chloride loading, and U-pH was remeasured the next morning. If U-pH after acid loading did not drop below 5.45, patients were diagnosed with abnormal distal renal tubular acidification. Normal values were obtained from 21 healthy controls. All LBM with dRTA were recommended alkali citrate in addition to conventional therapy of LBM, and follow-up DXAs were obtained until 2014. 85 LBM underwent NH4Cl loading. 42 LBM patients were diagnosed with incomplete dRTA (idRTA; prevalence 23.0 %). During follow-up (1.6-8 years) of idRTA-LBM patients, subjects adhering to alkali treatment tended to improve BMD at all sites measured, whereas BMD of non-adherent idRTA patients worsened/remained unchanged. (1) About one out of four patients with osteopenia/osteoporosis has idRTA. (2) Upon NH4Cl loading, idRTA patients do not lower urine pH normally, but show signs of increased acid-buffering by bone dissolution. (3) In idRTA patients with low bone mass on conventional therapy, additional long-term alkali treatment improves bone mass at lumbar spine and potentially at other bone sites. (4) All patients with low bone mass undergoing metabolic evaluation should be screened for idRTA.
Assuntos
Acidose Tubular Renal/epidemiologia , Acidose Tubular Renal/terapia , Álcalis/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Túbulos Renais Distais/fisiopatologia , Osteoporose/epidemiologia , Osteoporose/terapia , Acidose Tubular Renal/complicações , Acidose Tubular Renal/urina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cloreto de Amônio/farmacologia , Densitometria , Feminino , Seguimentos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Osteoporose/etiologia , Prevalência , Estudos Prospectivos , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/metabolismo , Coluna Vertebral/fisiopatologia , Adulto JovemRESUMO
Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP.
Assuntos
Inibidores de Calcineurina/toxicidade , Ciclosporina/toxicidade , Células Epiteliais/efeitos dos fármacos , Imunossupressores/toxicidade , Túbulos Renais Distais/efeitos dos fármacos , Alça do Néfron/efeitos dos fármacos , Membro 1 da Família 12 de Carreador de Soluto/agonistas , Animais , Arginina Vasopressina/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Células Epiteliais/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/fisiopatologia , Alça do Néfron/metabolismo , Alça do Néfron/fisiopatologia , Masculino , Ratos Brattleboro , Ratos Wistar , Renina/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/genética , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/agonistas , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Fatores de Tempo , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
A postnatal role of fibroblast growth factor receptor-1 (FGFR1) in the kidney is suggested by its binding to α-Klotho to form an obligate receptor for the hormone fibroblast growth factor-23 (FGF-23). FGFR1 is expressed in both the proximal and distal renal tubular segments, but its tubular specific functions are unclear. In this study, we crossed Fgfr1flox/flox mice with either gamma-glutamyltransferase-Cre (γGT-Cre) or kidney specific-Cre (Ksp-Cre) mice to selectively create proximal tubule (PT) and distal tubule (DT) Fgfr1 conditional knockout mice (designated Fgfr1PT-cKO and Fgfr1DT-cKO, respectively). Fgfr1PT-cKO mice exhibited an increase in sodium-dependent phosphate co-transporter expression, hyperphosphatemia, and refractoriness to the phosphaturic actions of FGF-23, consistent with a direct role of FGFR1 in mediating the proximal tubular phosphate responses to FGF-23. In contrast, Fgfr1DT-cKO mice unexpectedly developed hypercalciuria, secondary elevations of parathyroid hormone (PTH), hypophosphatemia and enhanced urinary phosphate excretion. Fgfr1PT-cKO mice also developed a curly tail/spina bifida-like skeletal phenotype, whereas Fgfr1DT-cKO mice developed renal tubular micro-calcifications and reductions in cortical bone thickness. Thus, FGFR1 has dual functions to directly regulate proximal and distal tubule phosphate and calcium reabsorption, indicating a physiological role of FGFR1 signaling in both phosphate and calcium homeostasis.
Assuntos
Cálcio/metabolismo , Túbulos Renais Distais/fisiopatologia , Túbulos Renais Proximais/fisiopatologia , Fosfatos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Animais , Transporte Biológico/genética , Osso e Ossos/anormalidades , Calcinose/genética , Cálcio/sangue , Cálcio/urina , Canais de Cálcio/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Deleção de Genes , Glucuronidase/metabolismo , Hipercalciúria/genética , Hiperfosfatemia/genética , Hipofosfatemia/genética , Transporte de Íons/genética , Proteínas Klotho , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hormônio Paratireóideo/metabolismo , Fosfatos/sangue , Fosfatos/urina , Disrafismo Espinal/genética , Canais de Cátion TRPV/metabolismoRESUMO
At least three renal tubular segments are involved in the pathophysiology of salt-losing tubulopathies (SLTs). Whether the pathogenesis starts either in the thick ascending limb of the loop of Henle (TAL) or in the distal convoluted tubule (DCT), it is the function of the downstream-localized aldosterone sensitive distal tubule (ASDT) to contribute to the adaptation process. In isolated TAL defects (loop disorders) ASDT adaptation is supported by upregulation of DCT, whereas in DCT disorders the ASDT is complemented by upregulation of TAL function. This upregulation has a major impact on the clinical presentation of SLT patients. Taking into account both the symptoms and signs of primary tubular defect and of the secondary reactions of adaptation, a clinical diagnosis can be made that eventually leads to an appropriate therapy. In addition to salt wasting, as occurs in all SLTs, characteristic features of loop disorders are hypo- or isosthenuric polyuria and hypercalciuria, whereas characteristics of DCT disorders are hypokalemia and (symptomatic) hypomagnesemia. In both SLT categories, replacement of urinary losses is the primary goal of treatment. In loop disorders COX inhibitors are also recommended to mitigate polyuria, and in DCT disorders magnesium supplementation is essential for effective treatment. Of note, the combination of a salt- and potassium-rich diet together with an adequate fluid intake is always the basis of long-term treatment in all SLTs.