RESUMEN
The kidney controls systemic inorganic phosphate (Pi) levels by adapting reabsorption to Pi intake. Renal Pi reabsorption is mostly mediated by sodium-phosphate cotransporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) that are tightly controlled by various hormones including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). PTH and FGF23 rise in response to Pi intake and decrease NaPi-IIa and NaPi-IIc brush border membrane abundance enhancing phosphaturia. Phosphaturia and transporter regulation occurs even in the absence of PTH and FGF23 signaling. The calcium-sensing receptor (CaSR) regulates PTH and FGF23 secretion, and may also directly affect renal Pi handling. Here, we combined pharmacological and genetic approaches to examine the role of the CaSR in the acute phosphaturic response to Pi loading. Animals pretreated with the calcimimetic cinacalcet were hyperphosphatemic, had blunted PTH levels upon Pi administration, a reduced Pi-induced phosphaturia, and no Pi-induced NaPi-IIa downregulation. The calcilytic NPS-2143 exaggerated the PTH response to Pi loading but did not abolish Pi-induced downregulation of NaPi-IIa. In mice with a dominant inactivating mutation in the Casr (CasrBCH002), baseline NaPi-IIa expression was higher, whereas downregulation of transporter expression was blunted in double CasrBCH002/PTH knockout (KO) transgenic animals. Thus, in response to an acute Pi load, acute modulation of the CaSR affects the endocrine and renal response, whereas chronic genetic inactivation, displays only subtle differences in the downregulation of NaPi-IIa and NaPi-IIc renal expression. We did not find evidence that the CaSR impacts on the acute renal response to oral Pi loading beyond its role in regulating PTH secretion.NEW & NOTEWORTHY Consumption of phosphate-rich diets causes an adaptive response of the body leading to the urinary excretion of phosphate. The underlying mechanisms are still poorly understood. Here, we examined the role of the calcium-sensing receptor (CaSR) that senses both calcium and phosphate. We confirmed that the receptor increases the secretion of parathyroid hormone involved in stimulating urinary phosphate excretion. However, we did not find any evidence for a role of the receptor beyond this function.
Asunto(s)
Factor-23 de Crecimiento de Fibroblastos , Riñón , Ratones Noqueados , Hormona Paratiroidea , Fosfatos , Receptores Sensibles al Calcio , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc , Receptores Sensibles al Calcio/metabolismo , Receptores Sensibles al Calcio/genética , Animales , Hormona Paratiroidea/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Fosfatos/metabolismo , Riñón/metabolismo , Riñón/efectos de los fármacos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética , Ratones , Reabsorción Renal/efectos de los fármacos , Masculino , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Ratones Endogámicos C57BLRESUMEN
The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Modelos Biológicos , Transportador 1 de Sodio-Glucosa , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/farmacocinética , Humanos , Compuestos de Bencidrilo/farmacocinética , Compuestos de Bencidrilo/orina , Transportador 1 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Glucosa/metabolismo , Masculino , Transportador 2 de Sodio-Glucosa/metabolismo , Adulto , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Reabsorción Renal/efectos de los fármacos , Riñón/metabolismo , Glucosuria , Femenino , Persona de Mediana EdadRESUMEN
PURPOSE: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH. METHODS: After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab. RESULTS: Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9â ±â 0.1 (least squares meanâ ±â SE; Pâ <â 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline Pâ <â 0.0001). Most adverse events were mild to moderate in severity. MAIN CONCLUSIONS: In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab. CLINICALTRIALS.GOV: NCT02163577.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Factor-23 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/efectos adversos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Raquitismo Hipofosfatémico Familiar/sangre , Raquitismo Hipofosfatémico Familiar/diagnóstico , Femenino , Factor-23 de Crecimiento de Fibroblastos/metabolismo , Humanos , Masculino , Fosfatos/sangre , Fosfatos/metabolismo , Reabsorción Renal/efectos de los fármacos , Índice de Severidad de la EnfermedadRESUMEN
Fine tuning of Na+ reabsorption takes place along the aldosterone-sensitive distal nephron, which includes the collecting duct (CD), where it is mainly regulated by aldosterone. In the CD, Na+ reabsorption is mediated by the epithelial Na+ channel and Na+ pump (Na+-K+-ATPase). Paracellular ion permeability is mainly dependent on tight junction permeability. Claudin-8 is one of the main tight junction proteins expressed along the aldosterone-sensitive distal nephron. We have previously shown a coupling between transcellular Na+ reabsorption and paracellular Na+ barrier. We hypothesized that aldosterone controls the expression levels of both transcellular Na+ transporters and paracellular claudin-8 in a coordinated manner. Here, we show that aldosterone increased mRNA and protein levels as well as lateral membrane localization of claudin-8 in cultured CD principal cells. The increase in claudin-8 mRNA levels in response to aldosterone was prevented by preincubation with 17-hydroxyprogesterone, a mineralocorticoid receptor antagonist, and by inhibition of transcription with actinomycin D. We also showed that a low-salt diet, which stimulated aldosterone secretion, was associated with increased claudin-8 abundance in the mouse kidney. Reciprocally, mice subjected to a high-salt diet, which inhibits aldosterone secretion, or treated with spironolactone, a mineralocorticoid receptor antagonist, displayed decreased claudin-8 expression. Inhibition of glycogen synthase kinase-3, Lyn, and Abl signaling pathways prevented the effect of aldosterone on claudin-8 mRNA and protein abundance, suggesting that signaling of protein kinases plays a permissive role on the transcriptional activity of the mineralocorticoid receptor. This study shows that signaling via multiple protein kinases working in concert mediates aldosterone-induced claudin-8 expression in the CD.NEW & NOTEWORTHY In this study, we showed that aldosterone modulates claudin-8 expression in cultured collecting duct principal cells and in the mouse kidney. The upregulation of claudin-8 expression in response to aldosterone is dependent on at least glycogen synthase kinase-3, Lyn, and Abl signaling pathways, indicating the participation of multiple protein kinases to the effect of aldosterone.
Asunto(s)
Aldosterona/farmacología , Claudinas/metabolismo , Túbulos Renales Colectores/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Sodio/metabolismo , Animales , Línea Celular , Claudinas/genética , Dieta Hiposódica , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/metabolismo , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Túbulos Renales Colectores/citología , Túbulos Renales Colectores/metabolismo , Ratones , Antagonistas de Receptores de Mineralocorticoides/farmacología , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-abl/metabolismo , Sodio en la Dieta/toxicidad , Transcripción Genética , Regulación hacia Arriba , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismoRESUMEN
BACKGROUND: Dotinurad is a selective urate reabsorption inhibitor (SURI), which selectively inhibits URAT1 to lower serum uric acid levels in patients with hyperuricemia. Herein, the effects of dotinurad were compared among patient groups with different stages of renal dysfunction. METHODS: Patient data from four clinical trials were pooled and divided into four groups according to the stage of renal dysfunction to compare the effects of dotinurad at different stages. The grouping (stages G1-G3b) was based on the estimated glomerular filtration rate (eGFR) of the patients. In addition, patient data from a long-term study (34 or 58 weeks) were evaluated in the same manner. RESULTS: In the pooled analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 64.7-100.0% at a dose of 2 or 4 mg. In the long-term analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 60.0-100.0% at a dose of 2 or 4 mg. Although the outcomes in stage G3b were worse due to higher baseline serum uric acid levels, satisfactory outcomes were observed in all stages. Even in stages G3a and G3b, when renal function declined, the eGFR remained constant throughout the dose period. CONCLUSION: The efficacy of dotinurad was confirmed in hyperuricemic patients with normal renal function (stage G1) and mild to moderate renal dysfunction (stage G2-G3b). Dotinurad was found to be effective in the treatment of hyperuricemia in patients with mild to moderate renal dysfunction.
Asunto(s)
Benzotiazoles/uso terapéutico , Hiperuricemia/tratamiento farmacológico , Enfermedades Renales/fisiopatología , Riñón/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Ácido Úrico/sangre , Uricosúricos/uso terapéutico , Adulto , Anciano , Benzotiazoles/efectos adversos , Biomarcadores/sangre , Ensayos Clínicos como Asunto , Femenino , Tasa de Filtración Glomerular , Humanos , Hiperuricemia/sangre , Hiperuricemia/diagnóstico , Hiperuricemia/fisiopatología , Riñón/metabolismo , Riñón/fisiopatología , Enfermedades Renales/diagnóstico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Uricosúricos/efectos adversosRESUMEN
Anticholinergics, therapeutic agents for overactive bladder, are clinically suggested to reduce urine output. We investigated whether this effect is due to bladder or kidney urine reabsorption. Various solutions were injected into the bladder of urethane-anesthetized SD rats. The absorption rate for 2 h was examined following the intravenous administration of the anticholinergics imidafenacin (IM), atropine (AT), and tolterodine (TO). The bilateral ureter was then canulated and saline was administered to obtain a diuretic state. Anticholinergics or 1-deamino-[8-D-arginine]-vasopressin (dDAVP) were intravenously administered. After the IM and dDAVP administrations, the rat kidneys were immunostained with AQP2 antibody, and intracellular cAMP was measured. The absorption rate was ~ 10% of the saline injected into the bladder and constant even when anticholinergics were administered. The renal urine among peaked 2 h after the saline administration. Each of the anticholinergics significantly suppressed the urine production in a dose-dependent manner, as did dDAVP. IM and dDAVP increased the intracellular cAMP levels and caused the AQP2 molecule to localize to the collecting duct cells' luminal side. The urinary reabsorption mechanism through the bladder epithelium was not activated by anticholinergic administration. Thus, anticholinergics suppress urine production via an increase in urine reabsorption in the kidneys' collecting duct cells via AQP2.
Asunto(s)
Antagonistas Colinérgicos/farmacología , Riñón/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Animales , Fármacos Antidiuréticos/efectos adversos , Fármacos Antidiuréticos/farmacología , Acuaporina 2/metabolismo , AMP Cíclico/metabolismo , Desamino Arginina Vasopresina/efectos adversos , Desamino Arginina Vasopresina/farmacología , Electrólitos/metabolismo , Femenino , Riñón/metabolismo , Concentración Osmolar , Ratas Sprague-Dawley , Reabsorción Renal/fisiología , Sodio/orina , Vejiga Urinaria/efectos de los fármacos , Micción/efectos de los fármacosRESUMEN
Inhibitors of the main proximal tubular Na-glucose cotransporter (SGLT2) mitigate diabetic glomerular hyperfiltration and have been approved by the United States Food and Drug Administration for slowing the progression of diabetic kidney disease. It has been proposed that SGLT2 inhibitors improve hard renal outcomes by reducing glomerular capillary pressure (PGC) via a tubuloglomerular feedback (TGF) response to a decrease in proximal reabsorption (Jprox). However, the effect of SGLT2 inhibition on PGC has not been measured. Here, we studied the effects of acute SGLT2 blockade (ertugliflozin) on Jprox and glomerular hemodynamics in two-period micropuncture experiments using streptozotocin-induced diabetic rats fed high- or low-NaCl diets. PGC was measured by direct capillary puncture or computed from tubular stop-flow pressure (PSF). TGF is intact while measuring PGC directly but rendered inoperative when measuring PSF. Acute SGLT2 inhibitor reduced Jprox by â¼30%, reduced PGC by 5-8 mmHg, and reduced glomerular filtration rate (GFR) by â¼25% (all P < 0.0001) but had no effect on PSF. The decrease in PGC was larger with the low-NaCl diet (8 vs. 5 mmHg, P = 0.04) where PGC was higher to begin with (54 vs. 50 mmHg, P = 0.003). Greater decreases in PGC corresponded, unexpectedly, to lesser decreases in GFR (P = 0.04). In conclusion, these results confirm expectations that PGC would decline in response to acute SGLT2 inhibition and that a functioning TGF system is required for this. We infer a contribution of postglomerular vasorelaxation to the TGF responses where decreases in PGC were large and decreases in GFR were small.NEW & NOTEWORTHY It has been theorized that Na-glucose cotransporter (SGLT2) blockade slows progression of diabetic kidney disease by reducing physical strain on the glomerulus. This is the first direct measurement of intraglomerular pressure during SGLT2 blockade. Findings confirmed that SGLT2 blockade does reduce glomerular capillary pressure, that this is mediated through tubuloglomerular feedback, and that the tubuloglomerular feedback response to SGLT2 blockade involves preglomerular vasoconstriction and postglomerular vasorelaxation.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Hemodinámica/efectos de los fármacos , Glomérulos Renales/irrigación sanguínea , Circulación Renal/efectos de los fármacos , Cloruro de Sodio Dietético/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/fisiopatología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Dieta Hiposódica , Progresión de la Enfermedad , Tasa de Filtración Glomerular/efectos de los fármacos , Masculino , Punciones , Ratas Wistar , Reabsorción Renal/efectos de los fármacos , Cloruro de Sodio Dietético/metabolismo , Cloruro de Sodio Dietético/toxicidad , EstreptozocinaRESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the latest introduction into the armamentarium of diabetes care in the present decade. By virtue of their beneficial effects, such as blood pressure-lowering, bodyweight reduction and significant renal and cardioprotective effects which extends beyond their glycaemic control effects, SGLT2i have become one of the most preferred oral antihyperglycaemic agents of recent times. However, they can influence tubular handling of electrolytes that can result in some electrolyte disturbances such as alteration in the serum levels of magnesium, potassium and phosphate levels. Some of these changes are mild or transient and may not have significant clinical implications. The underlying putative mechanism(s) responsible for disturbances of electrolytes are yet to be deciphered. In this review, we aim to describe electrolytes and acid-base abnormalities due to SGLT2i as well as to elucidate the underlying mechanism.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Electrólitos , Humanos , Hipoglucemiantes/farmacología , Eliminación Renal/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Sodio , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
This study was designed to investigate the effects and underlying mechanisms of Astaxanthin (AST) on high-fructose-induced hyperuricemia (HUA) from the perspectives of the uric acid (UA) synthesis and excretion in rat models. Following six weeks of a 10% fructose diet, the level of serum UA effectively decreased in the AST groups as compared to the model group. The enzymatic activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) were significantly inhibited, and the mRNA expression levels of XOD and ADA significantly decreased after the AST administration. These results suggested that the AST reduced UA synthesis by inhibiting the mRNA expressions and enzyme activities of XOD and ADA, thereby contributing to HUA improvement. On the hand, the relative expressions of the mRNA and protein of kidney reabsorption transport proteins (GLUT9 and URAT1) were significantly down-regulated by AST, while that of the kidney secretion proteins (OAT1, OAT3 and ABCG2) were significantly up-regulated by AST. These results indicated that the AST promoted UA excretion by regulating the urate transport proteins, and thus alleviated HUA. This study suggested that the AST could serve as an effective alternative to traditional medicinal drugs for the prevention of fructose-induced HUA.
Asunto(s)
Inhibidores de la Adenosina Desaminasa/farmacología , Adenosina Desaminasa/metabolismo , Hiperuricemia/prevención & control , Proteínas de Transporte de Membrana/efectos de los fármacos , Ácido Úrico/sangre , Xantina Oxidasa/antagonistas & inhibidores , Adenosina Desaminasa/genética , Animales , Biomarcadores/sangre , Biomarcadores/orina , Modelos Animales de Enfermedad , Fructosa , Hiperuricemia/inducido químicamente , Hiperuricemia/enzimología , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratas Sprague-Dawley , Reabsorción Renal/efectos de los fármacos , Ácido Úrico/orina , Xantina Oxidasa/genética , Xantina Oxidasa/metabolismo , Xantófilas/farmacologíaRESUMEN
Acidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. We examined the effect of lipopolysaccharide (LPS), on HCO3 absorption in isolated perfused rabbit OMCDi. LPS caused a ~ 40% decrease in HCO3 absorption, providing a mechanism for E. coli pyelonephritis-induced acidosis. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and Wortmannin, a phosphoinositide 3-kinase inhibitor, prevented the LPS-mediated decrease, demonstrating the role of TLR4-PI3-kinase signaling and providing proof-of-concept for therapeutic interventions aimed at ameliorating OMCDi dysfunction and pyelonephritis-induced acidosis.
Asunto(s)
Bicarbonatos/metabolismo , Lipopolisacáridos/metabolismo , Reabsorción Renal/efectos de los fármacos , Acidosis Tubular Renal/metabolismo , Acidosis Tubular Renal/fisiopatología , Animales , Bicarbonatos/química , Escherichia coli/metabolismo , Femenino , Riñón/metabolismo , Médula Renal/metabolismo , Túbulos Renales Colectores/metabolismo , Lípido A/análogos & derivados , Lípido A/metabolismo , Lipopolisacáridos/farmacología , Asa de la Nefrona/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/metabolismo , Pielonefritis/metabolismo , Conejos , Transducción de Señal/efectos de los fármacosRESUMEN
Chronic kidney disease (CKD) has significant effects on renal clearance (CLr ) of drugs. Physiologically-based pharmacokinetic (PBPK) models have been used to predict CKD effects on transporter-mediated renal active secretion and CLr for hydrophilic nonpermeable compounds. However, no studies have shown systematic PBPK modeling of renal passive reabsorption or CLr for hydrophobic permeable drugs in CKD. The goal of this study was to expand our previously developed and verified mechanistic kidney model to develop a universal model to predict changes in CLr in CKD for permeable and nonpermeable drugs that accounts for the dramatic nonlinear effect of CKD on renal passive reabsorption of permeable drugs. The developed model incorporates physiologically-based tubular changes of reduced water reabsorption/increased tubular flow rate per remaining functional nephron in CKD. The final adaptive kidney model successfully (absolute fold error (AFE) all < 2) predicted renal passive reabsorption and CLr for 20 permeable and nonpermeable test compounds across the stages of CKD. In contrast, use of proportional glomerular filtration rate reduction approach without addressing tubular adaptation processes in CKD to predict CLr generated unacceptable CLr predictions (AFE = 2.61-7.35) for permeable compounds in severe CKD. Finally, the adaptive kidney model accurately predicted CLr of para-amino-hippuric acid and memantine, two secreted compounds, in CKD, suggesting successful integration of active secretion into the model, along with passive reabsorption. In conclusion, the developed adaptive kidney model enables mechanistic predictions of in vivo CLr through CKD progression without any empirical scaling factors and can be used for CLr predictions prior to assessment of drug disposition in renal impairment.
Asunto(s)
Riñón/metabolismo , Tasa de Depuración Metabólica/efectos de los fármacos , Insuficiencia Renal Crónica/sangre , Reabsorción Renal/efectos de los fármacos , Transporte Biológico , Progresión de la Enfermedad , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Riñón/fisiología , Memantina/metabolismo , Modelos Biológicos , Farmacocinética , Valor Predictivo de las Pruebas , Insuficiencia Renal/metabolismo , Insuficiencia Renal Crónica/clasificación , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Ácido p-Aminohipúrico/metabolismoRESUMEN
Hyperuricemia is mainly the result of relative underexcretion of urate. Urate is mainly eliminated by kidney and several important transporters expressed on the membrane of renal tubular cells involved in urate excretion. Olsalazine sodium was screened from 3167 authorized small compounds/drugs, targeting xanthine oxidoreductase. In previous study, we reported that olsalazine sodium significantly reduced the serum urate levels, and the anti-hyperuricemic activity linked with inhibiting urate formation by reducing the activity of xanthine oxidoreductase. The current research aimed to assess olsalazine sodium renal urate excretion and likely molecular mechanism. The results showed that administration of olsalazine sodium 5.0 mg/kg decreased the levels of serum urate in hyperuricemic rats, and noticeably improved the fractional excretion of urate and urate clearance, exhibiting an uricosuric action. Moreover, olsalazine sodium (2.5, 5.0, 10.0 mg/kg) reduced the level of blood urea nitrogen in rats. Further study showed that olsalazine sodium reduced the mRNA expression of urate reabsorptive transporter glucose transporter 9 (GLUT9), increased the mRNA expression of urate secretory transporters, organic anion transporter 1 (OAT1), OAT3 and type 1 sodium-dependent phosphate transporter (NPT1) as well as the protein expression of OAT3 in the kidney in hyperuricemic mice. In conclusion, olsalazine sodium exhibited a promotion of urate excretion in kidney by increasing the expression of OAT3.
Asunto(s)
Ácidos Aminosalicílicos/farmacología , Hiperuricemia/tratamiento farmacológico , Transportadores de Anión Orgánico Sodio-Independiente/agonistas , Eliminación Renal/efectos de los fármacos , Ácido Úrico/metabolismo , Ácidos Aminosalicílicos/uso terapéutico , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Creatinina/orina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Proteínas Facilitadoras del Transporte de la Glucosa/antagonistas & inhibidores , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Hiperuricemia/sangre , Hiperuricemia/fisiopatología , Hiperuricemia/orina , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/fisiopatología , Masculino , Ratones , Proteínas de Transporte de Monosacáridos/antagonistas & inhibidores , Proteínas de Transporte de Monosacáridos/metabolismo , Proteína 1 de Transporte de Anión Orgánico/agonistas , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ratas , Ratas Sprague-Dawley , Eliminación Renal/fisiología , Reabsorción Renal/efectos de los fármacos , Reabsorción Renal/fisiología , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo I/agonistas , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo I/metabolismo , Ácido Úrico/sangre , Ácido Úrico/orinaRESUMEN
The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous GLP-1R signaling influences the regulation of BP. To this end, SHRs (spontaneously hypertensive rats) and Wistar rats were treated with the GLP-1R antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving the GLP-1R agonist Ex4 (exenatide) were used as an additional control. We found that blockade of baseline GLP-1R signaling by Ex9 increased systolic BP in both SHR and Wistar rats, compared with vehicle-treated animals, while Ex4 only reduced systolic BP in SHR. Higher systolic BP induced by Ex9 was accompanied by reduced lithium clearance and lower levels of NHE3 (Na+/H+ exchanger isoform 3) phosphorylation at the serine 552, indicative of increased proximal tubule sodium reabsorption. Additionally, urinary AGT (angiotensinogen) and renal cortical concentration of Ang II (angiotensin II) were enhanced by Ex9. Conversely, Ex4 decreased both urinary AGT and cortical Ang II but exclusively in SHRs. Moreover, both SHR and Wistar rats treated with Ex9 displayed hyperinsulinemia as compared with vehicle-treated rats, whereas Ex4 reduced fasting insulin concentration in SHR. Collectively, these results suggest that endogenous GLP-1R signaling exerts a physiologically relevant effect on BP control, which may be attributable, in part, to its tonic actions on the proximal tubule NHE3-mediated sodium reabsorption, intrarenal renin-angiotensin system, and insulin sensitivity. The possible role of impaired GLP-1R signaling in the pathogenesis of hypertension warrants further investigation.
Asunto(s)
Angiotensina II/metabolismo , Presión Sanguínea , Receptor del Péptido 1 Similar al Glucagón , Hipertensión , Eliminación Renal , Reabsorción Renal , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Exenatida/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Isoformas de Proteínas , Ratas , Ratas Endogámicas SHR , Eliminación Renal/efectos de los fármacos , Eliminación Renal/fisiología , Reabsorción Renal/efectos de los fármacos , Reabsorción Renal/fisiología , Transducción de Señal , Intercambiador 3 de Sodio-Hidrógeno/metabolismoRESUMEN
Lithium is mainly excreted into urine, and a large fraction of lithium filtered through glomeruli is reabsorbed in the proximal tubule. However, the mechanisms responsible for lithium reabsorption remain unclear. We previously reported that the reabsorption of lithium was biphasic in rats, and that foscarnet inhibited lithium reabsorption with a high affinity type. We herein evaluated the effects of acetazolamide and foscarnet on the renal excretion of lithium in rats treated with lithium chloride at 2 doses. In rats intravenously injected with a bolus of 25 mg/kg lithium chloride, acetazolamide facilitated the urinary excretion of lithium, and increased the fractional excretion of lithium from 0.446 to 0.953, near the theoretically maximum value. At a dose of 2.5 mg/kg lithium chloride, the fractional excretion of lithium was 0.241 in control rats, 0.420 in rats administered acetazolamide, and 0.976 in rats administered acetazolamide and foscarnet. These results showed the potent inhibition of lithium reabsorption by acetazolamide and foscarnet in rats. And, it was exhibited that the effects of acetazolamide on lithium reabsorption differed with the dosages of lithium administered.
Asunto(s)
Acetazolamida/farmacología , Foscarnet/farmacología , Túbulos Renales Proximales/efectos de los fármacos , Cloruro de Litio/farmacología , Reabsorción Renal/efectos de los fármacos , Animales , Antivirales/farmacología , Modelos Animales de Enfermedad , Diuréticos/farmacología , Interacciones Farmacológicas , Túbulos Renales Proximales/metabolismo , Cloruro de Litio/antagonistas & inhibidores , Cloruro de Litio/farmacocinética , Masculino , Ratas , Ratas WistarRESUMEN
The beneficial effects of fatty acids (FAs) on human health have attracted widespread interest. However, little is known about the impact of FAs on the handling of urate, the end-product of human purine metabolism, in the body. Increased serum urate levels occur in hyperuricemia, a disease that can lead to gout. In humans, urate filtered by the glomerulus of the kidney is majorly re-absorbed from primary urine into the blood via the urate transporter 1 (URAT1)-mediated pathway. URAT1 inhibition, thus, contributes to decreasing serum urate concentration by increasing net renal urate excretion. Here, we investigated the URAT1-inhibitory effects of 25 FAs that are commonly contained in foods or produced in the body. For this purpose, we conducted an in vitro transport assay using cells transiently expressing URAT1. Our results showed that unsaturated FAs, especially long-chain unsaturated FAs, inhibited URAT1 more strongly than saturated FAs. Among the tested unsaturated FAs, eicosapentaenoic acid, α-linolenic acid, and docosahexaenoic acid exhibited substantial URAT1-inhibitory activities, with half maximal inhibitory concentration values of 6.0, 14.2, and 15.2 µM, respectively. Although further studies are required to investigate whether the ω-3 polyunsaturated FAs can be employed as uricosuric agents, our findings further confirm FAs as nutritionally important substances influencing human health.
Asunto(s)
Ácidos Grasos Omega-3/farmacología , Glomérulos Renales/metabolismo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico/fisiología , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/fisiología , Reabsorción Renal/efectos de los fármacos , Ácido Úrico/metabolismo , Células Cultivadas , Ácidos Docosahexaenoicos/farmacología , Relación Dosis-Respuesta a Droga , Ácido Eicosapentaenoico/farmacología , Humanos , Hiperuricemia/sangre , Eliminación Renal/efectos de los fármacos , Ácido Úrico/sangre , Ácido alfa-Linolénico/farmacologíaRESUMEN
Angiotensin II (ANG II) stimulates proximal nephron transport via activation of classical protein kinase C (PKC) isoforms. Acute fructose treatment stimulates PKC and dietary fructose enhances ANG II's ability to stimulate Na+ transport, but the mechanisms are unclear. We hypothesized that dietary fructose enhances ANG II's ability to stimulate renal proximal tubule Na+ reabsorption by augmenting PKC-α activation and increases in intracellular Ca2+. We measured total and isoform-specific PKC activity, basal and ANG II-stimulated oxygen consumption, a surrogate of Na+ reabsorption, and intracellular Ca2+ in proximal tubules from rats given either 20% fructose in their drinking water (fructose group) or tap water (control group). Total PKC activity was measured by ELISA. PKC-α, PKC-ß, and PKC-γ activities were assessed by measuring particulate-to-soluble ratios. Intracelluar Ca2+ was measured using fura 2. ANG II stimulated total PKC activity by 53 ± 15% in the fructose group but not in the control group (-15 ± 11%, P < 0.002). ANG II stimulated PKC-α by 0.134 ± 0.026 but not in the control group (-0.002 ± 0.020, P < 0.002). ANG II increased PKC-γ activity by 0.008 ± 0.003 in the fructose group but not in the control group (P < 0.046). ANG II did not stimulate PKC-ß in either group. ANG II increased Na+ transport by 454 ± 87 nmol·min-1·mg protein-1 in fructose group, and the PKC-α/ß inhibitor Gö6976 blocked this increase (-96 ± 205 nmol·min-1·mg protein-1, P < 0.045). ANG II increased intracellular Ca2+ by 148 ± 53 nM in the fructose group but only by 43 ± 10 nM in the control group (P < 0.035). The intracellular Ca2+ chelator BAPTA blocked the ANG II-induced increase in Na+ transport in the fructose group. We concluded that dietary fructose enhances ANG II's ability to stimulate renal proximal tubule Na+ reabsorption by augmenting PKC-α activation via elevated increases in intacellular Ca2+.
Asunto(s)
Angiotensina II/farmacología , Azúcares de la Dieta/administración & dosificación , Fructosa/administración & dosificación , Túbulos Renales Proximales/efectos de los fármacos , Proteína Quinasa C-alfa/metabolismo , Reabsorción Renal/efectos de los fármacos , Sodio/metabolismo , Animales , Calcio/metabolismo , Activación Enzimática , Túbulos Renales Proximales/enzimología , Masculino , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. SUMMARY: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.
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Anemia/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Eritropoyetina/metabolismo , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Anemia/sangre , Anemia/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/sangre , Eritropoyesis/efectos de los fármacos , Hematócrito , Hemoglobinas/análisis , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Reabsorción Renal/efectos de los fármacos , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
Adenosine plays an important role in various aspects of kidney physiology, but the specific targets and mechanisms of actions are not completely understood. The collecting duct has the highest expression of adenosine receptors, particularly adenosine A1 receptors (A1Rs). Interstitial adenosine levels are greatly increased up to a micromolar range in response to dietary salt loading. We have previously shown that the basolateral membrane of principal cells has primarily K+ conductance mediated by Kir4.1/5.1 channels to mediate K+ recycling and to set up a favorable driving force for Na+/K+ exchange (47). Intercalated cells express the Cl- ClC-K2/b channel mediating transcellular Cl- reabsorption. Using patch-clamp electrophysiology in freshly isolated mouse collecting ducts, we found that acute application of adenosine reversely inhibits ClC-K2/b open probability from 0.31 ± 0.04 to 0.17 ± 0.06 and to 0.10 ± 0.05 for 1 and 10 µM, respectively. In contrast, adenosine (10 µM) had no measureable effect on Kir4.1/5.1 channel activity in principal cells. The inhibitory effect of adenosine on ClC-K2/b was abolished in the presence of the A1R blocker 8-cyclopentyl-1,3-dipropylxanthine (10 µM). Consistently, application of the A1R agonist N6-cyclohexyladenosine (1 µM) recapitulated the inhibitory action of adenosine on ClC-K2/b open probability. The effects of adenosine signaling in the collecting duct were independent from its purinergic counterpartner, ATP, having no measurable actions on ClC-K2/b and Kir4.1/5.1. Overall, we demonstrated that adenosine selectively inhibits ClC-K2/b activity in intercalated cells by targeting A1Rs. We propose that inhibition of transcellular Cl- reabsorption in the collecting duct by adenosine would aid in augmenting NaCl excretion during high salt intake.
Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Adenosina/farmacología , Proteínas de Transporte de Anión/antagonistas & inhibidores , Canales de Cloruro/antagonistas & inhibidores , Cloruros/metabolismo , Túbulos Renales Colectores/efectos de los fármacos , Receptor de Adenosina A1/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Animales , Proteínas de Transporte de Anión/metabolismo , Señalización del Calcio/efectos de los fármacos , Células Cultivadas , Canales de Cloruro/metabolismo , Túbulos Renales Colectores/citología , Túbulos Renales Colectores/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones Endogámicos C57BL , Receptor de Adenosina A1/metabolismoRESUMEN
Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium-glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is linked to a diuretic and natriuretic effect that activates compensatory increases in fluid and food intake to stabilize body fluid volume (BFV). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear. Type 2 diabetic Goto-Kakizaki (GK) rats were treated with vehicle or 0.01% (in diet) ipragliflozin with free access to fluid and food. After 8 weeks, GK rats were placed in metabolic cages for 24-hr. Ipragliflozin decreased body weight, serum glucose and systolic blood pressure, and increased fluid and food intake, urinary glucose and Na+ excretion, urine volume, and renal osmolar clearance, as well as urine vasopressin and solute-free water reabsorption (TcH2O). BFV, measured by bioimpedance spectroscopy, and fluid balance were similar among the two groups. Urine vasopressin in ipragliflozin-treated rats was negatively and positively associated with fluid balance and TcH2O, respectively. Ipragliflozin increased the renal membrane protein expression of SGLT2, aquaporin (AQP) 2 phosphorylated at Ser269 and vasopressin V2 receptor. The expression of SGLT1, GLUT2, AQP1, and AQP2 was similar between the groups. In conclusion, the SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin-induced TcH2O in proportion to the reduced fluid balance to maintain BFV. These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain BFV.
Asunto(s)
Líquidos Corporales/metabolismo , Diuresis/fisiología , Ósmosis/fisiología , Reabsorción Renal/fisiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Vasopresinas/orina , Agua/metabolismo , Animales , Compartimentos de Líquidos Corporales/efectos de los fármacos , Compartimentos de Líquidos Corporales/metabolismo , Líquidos Corporales/efectos de los fármacos , Diuresis/efectos de los fármacos , Diuréticos Osmóticos/farmacología , Glucósidos/farmacología , Ósmosis/efectos de los fármacos , Ratas , Reabsorción Renal/efectos de los fármacos , Tiofenos/farmacologíaRESUMEN
The incidence of diabetes mellitus (DM) has increased alarmingly over the last decades. Despite taking measures aimed at controlling hyperglycaemia and blood pressure, the rate of end-stage renal disease (ESRD) is continually growing. Upon increased amounts of advanced glycation end products (AGEs) and their correspondent receptors (RAGEs), AGE-RAGE axis is over-activated in DM, being the first step in the initiation and propagation of inflammatory cascades. Meanwhile, HMGB1, released from damaged cells in the diabetic kidneys, is the most notable ligand for the highly expressed toll-like receptors (TLRs) and RAGEs. TLRs play an indispensable role in the pathogenesis of diabetic nephropathy. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are hypoglycaemic agents acting on the renal proximal tubules to prevent glucose reabsorption and therefore increase urinary glucose excretion. Besides improving glycaemic control, these hypoglycaemic agents possess direct renoprotective properties. Here, therefore, we review the most recent findings regarding interrelationship between SGLT2 inhibitors and HMGB1-TLR4 axis.