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1.
Clin Transl Sci ; 17(10): e70047, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39435882

RESUMEN

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss-Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK-CGNM analysis using reported autoradiography data ([14C]-LNG) in wild-type and Dpp-4-deficient rats, DPP-4-specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP-4 and the reabsorption clearance for LNG-DPP-4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP-4 expressions and in vitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high-affinity probe for DPP-4, comprehensive PBPK-CGNM analyses suggested a dynamic whole-body distribution of DPP-4, including its involvement in the renal reabsorption of LNG.


Asunto(s)
Dipeptidil Peptidasa 4 , Inhibidores de la Dipeptidil-Peptidasa IV , Linagliptina , Modelos Biológicos , Reabsorción Renal , Linagliptina/farmacocinética , Linagliptina/administración & dosificación , Animales , Humanos , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Ratas , Distribución Tisular , Masculino , Riñón/metabolismo , Ratones Noqueados , Ratones
2.
Biochem Biophys Res Commun ; 734: 150730, 2024 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-39366177

RESUMEN

A regulatory mechanism for SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule, is incompletely understood. Here, we report an important regulation of SLC family transporter by SETD2, a chromatin remodeling gene whose alterations have been found in a subset of kidney cancers. Kidney-specific inactivation of Setd2 resulted in hypovolemia with excessive urine excretion in mouse and interestingly, RNA-sequencing analysis of Setd2-deficient murine kidney exhibited decreased expressions of SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule. Importantly, inactivation of Setd2 in murine kidney displayed attenuated dapagliflozin-induced diuresis and glucose excretion, further supporting that SETD2 might regulate SLCfamily transporter-mediated sodium and glucose reabsorptions in renal tubule. These data uncover an important regulation of SLC family transporter by SETD2, which may illuminate a crosstalk between metabolism and epigenome in renal tubule.


Asunto(s)
Glucosa , N-Metiltransferasa de Histona-Lisina , Túbulos Renales , Sodio , Animales , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Glucosa/metabolismo , Ratones , Túbulos Renales/metabolismo , Sodio/metabolismo , Sodio/orina , Masculino , Ratones Noqueados , Proteínas Transportadoras de Solutos/metabolismo , Proteínas Transportadoras de Solutos/genética , Ratones Endogámicos C57BL , Reabsorción Renal
3.
Am J Physiol Renal Physiol ; 327(1): F77-F90, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38721663

RESUMEN

Pregnancy is associated with elevated demand of most nutrients, with many trace elements and minerals critical for the development of fetus. In particular, calcium (Ca2+) and magnesium (Mg2+) are essential for cellular function, and their deficiency can lead to impaired fetal growth. A key contributor to the homeostasis of these ions is the kidney, which in a pregnant rat undergoes major changes in morphology, hemodynamics, and molecular structure. The goal of this study is to unravel the functional implications of these pregnancy-induced changes in renal handling of Ca2+ and Mg2+, two cations that are essential in a healthy pregnancy. To achieve that goal, we developed computational models of electrolyte and water transport along the nephrons of a rat in mid and late pregnancy. Model simulations reveal a substantial increase in the reabsorption of Mg2+ along the proximal tubules and thick ascending limbs. In contrast, the reabsorption of Ca2+ is increased in the proximal tubules but decreased in the thick ascending limbs, due to the lower transepithelial concentration gradient of Ca2+ along the latter. Despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of Ca2+ and Mg2+ in pregnancy. Furthermore, we conducted simulations of hypocalcemia and hypomagnesemia. We found that hypocalcemia lowers Ca2+ excretion substantially more than Mg2+ excretion, with this effect being more pronounced in virgin rats than in pregnant ones. Conversely, hypomagnesemia reduces the excretion of Mg2+ and Ca2+ to more similar degrees. These differences can be explained by the greater sensitivity of the calcium-sensing receptor (CaSR) to Ca2+ compared with Mg2+.NEW & NOTEWORTHY A growing fetus' demands of minerals, notably calcium and magnesium, necessitate adaptations in pregnancy. In particular, the kidney undergoes major changes in morphology, hemodynamics, and molecular structure. This computational modeling study provides insights into how these pregnancy-induced renal adaptation impact calcium and magnesium transport along different nephron segments. Model simulations indicate that, despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of calcium and magnesium in pregnancy.


Asunto(s)
Calcio , Tasa de Filtración Glomerular , Riñón , Magnesio , Femenino , Embarazo , Animales , Magnesio/metabolismo , Magnesio/orina , Calcio/metabolismo , Calcio/orina , Riñón/metabolismo , Ratas , Simulación por Computador , Reabsorción Renal , Modelos Biológicos
4.
Int J Mol Sci ; 25(9)2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38731904

RESUMEN

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.


Asunto(s)
Fosfatos , Humanos , Fosfatos/metabolismo , Animales , Reabsorción Renal , Riñón/metabolismo , Túbulos Renales Proximales/metabolismo
5.
Am J Physiol Renal Physiol ; 326(5): F792-F801, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38545651

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 , Hormona Paratiroidea , Fosfatos , Receptores Sensibles al Calcio , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc , Animales , Masculino , Ratones , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Riñón/metabolismo , Riñón/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Hormona Paratiroidea/metabolismo , Fosfatos/metabolismo , Receptores Sensibles al Calcio/metabolismo , Receptores Sensibles al Calcio/genética , Reabsorción Renal/efectos de los fármacos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética
6.
J Clin Pharmacol ; 64(6): 672-684, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38363006

RESUMEN

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 Edad
8.
Clin J Am Soc Nephrol ; 17(2): 228-239, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35131929

RESUMEN

BACKGROUND AND OBJECTIVES: The estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance. RESULTS: Low TmP/GFR (<0.80 mmol/L) was observed in 1392 (67%) and 21 (27%) patients. Patients with lower TmP/GFR had more advanced heart failure, lower eGFR, and higher levels of tubular damage markers. The main determinant of lower TmP/GFR was higher fractional excretion of urea (P<0.001). Lower TmP/GFR was independently associated with higher risk of plasma NGAL doubling (odds ratio, 2.20; 95% confidence interval, 1.05 to 4.66; P=0.04) but not with deterioration of kidney function. Lower TmP/GFR was associated with higher risk of all-cause mortality (hazard ratio, 2.80; 95% confidence interval, 1.37 to 5.73; P=0.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P=0.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P=0.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P=0.004) but not after adjustment for eGFR change. CONCLUSIONS: TmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.


Asunto(s)
Insuficiencia Cardíaca/metabolismo , Túbulos Renales Proximales/metabolismo , Fosfatos/metabolismo , Reabsorción Renal , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad
9.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35173044

RESUMEN

The lungs and kidneys are pivotal organs in the regulation of body acid-base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO3- into the urine leads to metabolic alkalosis [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, Open Respir. Med. J. 6, 59-62 (2012)]. This is caused by defective HCO3- secretion in the ß-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020)]. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.


Asunto(s)
Alcalosis/fisiopatología , Fibrosis Quística/fisiopatología , Hipoventilación/fisiopatología , Equilibrio Ácido-Base/fisiología , Alcalosis/metabolismo , Animales , Bicarbonatos/metabolismo , Antiportadores de Cloruro-Bicarbonato , Fibrosis Quística/complicaciones , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/fisiología , Modelos Animales de Enfermedad , Femenino , Hipoventilación/etiología , Hipoventilación/metabolismo , Transporte Iónico , Riñón/metabolismo , Riñón/patología , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Eliminación Renal , Reabsorción Renal/fisiología
10.
Am J Physiol Renal Physiol ; 322(2): F225-F244, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35001663

RESUMEN

The renal response to acute hyperkalemia is mediated by increased K+ secretion within the connecting tubule (CNT), flux that is modulated by tubular effects (e.g., aldosterone) in conjunction with increased luminal flow. There is ample evidence that peritubular K+ blunts Na+ reabsorption in the proximal tubule, thick ascending Henle limb, and distal convoluted tubule (DCT). Although any such reduction may augment CNT delivery, the relative contribution of each is uncertain. The kidney model of this laboratory was recently advanced with representation of the cortical labyrinth and medullary ray. Model tubules capture the impact of hyperkalemia to blunt Na+ reabsorption within each upstream segment. However, this forces the question of the extent to which increased Na+ delivery is transmitted past the macula densa and its tubuloglomerular feedback (TGF) signal. Beyond increasing macula densa Na+ delivery, peritubular K+ is predicted to raise cytosolic Cl- and depolarize macula densa cells, which may also activate TGF. Thus, although the upstream reduction in Na+ transport may be larger, it appears that the DCT effect is critical to increasing CNT delivery. Beyond the flow effect, hyperkalemia reduces ammoniagenesis and reduced ammoniagenesis enhances K+ excretion. What this model provides is a possible mechanism. When cortical [Formula: see text] is taken up via peritubular Na+-K+([Formula: see text])-ATPase, it acidifies principal cells. Consequently, reduced ammoniagenesis increases principal cell pH, thereby increasing conductance of both the epithelial Na+ channel and renal outer medullary K+ channel, enhancing K+ excretion. In this model, the effect of aldosterone on principal cells, diminished DCT Na+ reabsorption, and reduced ammoniagenesis all provide relatively equal and additive contributions to renal K+ excretion.NEW & NOTEWORTHY Hyperkalemia blunts Na+ reabsorption along the nephron, and increased CNT Na+ delivery facilitates K+ secretion. The model suggests that tubuloglomerular feedback limits transmission of proximal effects past the macula densa, so that it is DCT transport that is critical. Hyperkalemia also reduces PCT ammoniagenesis, which enhances K+ excretion. The model suggests a mechanism, namely, that reduced cortical ammonia impacts CNT transport by raising cell pH and thus increasing both ENaC and ROMK conductance.


Asunto(s)
Amoníaco/metabolismo , Hiperpotasemia/metabolismo , Riñón/metabolismo , Modelos Biológicos , Potasio/sangre , Eliminación Renal , Reabsorción Renal , Sodio/metabolismo , Animales , Canales Epiteliales de Sodio/metabolismo , Retroalimentación Fisiológica , Concentración de Iones de Hidrógeno , Hiperpotasemia/sangre , Hiperpotasemia/fisiopatología , Riñón/fisiopatología , Canales de Potasio de Rectificación Interna/metabolismo , Ratas
11.
Am J Physiol Renal Physiol ; 322(2): F121-F137, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34894726

RESUMEN

Normal pregnancy is characterized by massive increases in plasma volume and electrolyte retention. Given that the kidneys regulate homeostasis of electrolytes and volume, the organ undergoes major adaptations in morphology, hemodynamics, and transport to achieve the volume and electrolyte retention required in pregnancy. These adaptations are complex, sometimes counterintuitive, and not fully understood. In addition, the demands of the developing fetus and placenta change throughout pregnancy. For example, during late pregnancy, K+ retention and thus enhanced renal K+ reabsorption are required despite many kaliuretic factors. The goal of this study was to unravel how known adaptive changes along the nephrons contribute to the ability of the kidney to meet volume and electrolyte requirements in mid and late pregnancy. We developed computational models of solute and water transport in the superficial nephron of the kidney of a rat in mid and late pregnancy. The midpregnant and late-pregnant rat superficial nephron models predicted that morphological adaptations and increased activity of Na+/H+ exchanger 3 (NHE3) and epithelial Na+ channel are essential for the enhanced Na+ reabsorption observed during pregnancy. Model simulations showed that for sufficient K+ reabsorption, increased activity of H+-K+-ATPase and decreased K+ secretion along the distal segments is required in both mid and late pregnancy. The model results also suggested that certain known sex differences in renal transporter pattern (e.g., the higher NHE3 protein abundance but lower activity in the proximal tubules of virgin female rats compared with male rats) may serve to better prepare females for the increased transport demand in pregnancy.NEW & NOTEWORTHY Normal pregnancy in mammals is generally characterized by massive changes in plasma volume and electrolyte retention. This study provides insights into how the volume and electrolyte requirement in different pregnancy stages are met by coordinated adaptive changes in the kidney. The model results also suggested that certain known sex differences in the renal transporter pattern may serve to better prepare females for the increased transport demand in pregnancy.


Asunto(s)
Células Epiteliales/metabolismo , Tasa de Filtración Glomerular , Modelos Biológicos , Nefronas/metabolismo , Potasio/metabolismo , Reabsorción Renal , Sodio/metabolismo , Equilibrio Hidroelectrolítico , Adaptación Fisiológica , Animales , Acuaporinas/metabolismo , Canales Epiteliales de Sodio/metabolismo , Femenino , Masculino , Nefronas/citología , Volumen Plasmático , Embarazo , Ratas , Factores Sexuales , Intercambiador 3 de Sodio-Hidrógeno/metabolismo
12.
J Clin Endocrinol Metab ; 107(3): 813-824, 2022 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-34636899

RESUMEN

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 0.9 ±â€…0.1 (least squares mean ±â€…SE; P < 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 P < 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 Enfermedad
14.
Am J Physiol Renal Physiol ; 321(5): F645-F655, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34605273

RESUMEN

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/metabolismo
15.
Theranostics ; 11(18): 9118-9132, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34522230

RESUMEN

Rationale: A robust radiopharmaceutical has high uptake in the target and low retention in non-target tissues. However, traditional tracers for renal imaging that chemically chelate 99mTc are excreted through the renal route with transient resident time in the kidney. Following a rational design approach, we constructed a protein-based radiotracer, designated PBT-Fc, to sequentially bind tubular neonatal Fc-receptor and subsequently proximal tubular basement membrane for its targeted sequestration in kidney parenchyma. In this process, the tracer participates in physiologic glomerular filtration and tubular reabsorption while escaping lysosomal catabolism and urinary clearance. Methods: To specifically target renal receptors in navigating the urinary passage in the kidney, we produced a recombinant fusion protein with two separate functional parts: a polybasic PBT segment derived from human Vascular Endothelial Growth Factor and Fc segment of IgG1. The chimeric fusion of PBT-Fc was labeled with radionuclide 99mTc and tested in rodent models of kidney diseases. Planar scintigraphy and single-photon emission computerized tomography (SPECT) were performed to evaluate renal-specificity of the tracer. Results: When injected in mouse and rat, following a brief 10 - 15 min dynamic redistribution phase in circulation, ~ 95% of the [99mTc]-PBT-Fc signal was concentrated in the kidney and lasted for hours without urinary loss or surrounding tissue activities. Long-lasting tracer signals in the kidney cortex in conjunction with SPECT greatly augmented the image quality in detecting pathological lesions in a variety of disease models, including ischemic acute kidney injury, drug-induced renal toxicity, and chronic kidney disease from renin-angiotensin system (RAS) overactivation. Conclusion: Exclusive renal retention of the recombinant radiotracer greatly facilitated static-phase signal acquisition by SPECT and achieved submillimeter spatial resolution of kidney alternations in glomerular and tubular disease models.


Asunto(s)
Riñón/diagnóstico por imagen , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Antígenos de Histocompatibilidad Clase I/metabolismo , Pruebas de Función Renal/métodos , Túbulos Renales/diagnóstico por imagen , Masculino , Ratones , Ratones Endogámicos BALB C , Trazadores Radiactivos , Radioisótopos/farmacocinética , Cintigrafía/métodos , Radiofármacos/farmacocinética , Ratas , Receptores Fc/metabolismo , Reabsorción Renal/fisiología , Tomografía Computarizada de Emisión de Fotón Único/métodos
16.
Artículo en Inglés | MEDLINE | ID: mdl-34530136

RESUMEN

The osmotic physiology of freshwater stingrays was investigated in fifteen species from white (WW), black (BW), and clearwater (CW) rivers of Brazilian hydrographic basins. Regardless of phylogeny, potamotrygonids collected in the BW (Negro, Jutai, Nhamunda, and Manacapuru rivers), and CW (Tapajos, Parana, Mutum, Demeni, and Branco rivers) exhibited lower levels of osmolytes and plasma osmolality than those from WW (Amazon estuary, Solimoes, and Tarauaca rivers). However, the gill and kidney Na+/K+-ATPase activities were higher in the potamotrygonid species from BW and CW than those from WW. These results may be related to the ability of the potamotrygonids to achieve high ion uptake from ion-poor waters, such as those of BW and/or CW. Additionally, the high kidney Na+/K+-ATPase activity may help to minimize ion loss and generate diluted urine. Thus, diffusional losses of salts are balanced by uptake of ions in the gill, and reabsorption by the kidney. The physiological traits showed a weak phylogenetic signal, which indicates a strong evolutionary convergence. Multivariate analyses revealed that variations in physiological traits has a significant association with the type of water, as well as its physical and chemical characteristics such as electric conductivity and pH. Therefore, the South American Neotropical freshwater stingrays adjust their osmoregulatory mechanisms according to the environment in which they live.


Asunto(s)
Electrólitos/metabolismo , Mitocondrias/metabolismo , Osmorregulación , Rajidae/metabolismo , Clima Tropical , Animales , Electrólitos/sangre , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Agua Dulce , Branquias/metabolismo , Riñón/metabolismo , Mitocondrias/genética , Ósmosis , Filogenia , Reabsorción Renal , Rajidae/sangre , Rajidae/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo
17.
Clin Exp Nephrol ; 25(12): 1336-1345, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34328574

RESUMEN

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 adversos
18.
Physiol Res ; 70(4): 655-659, 2021 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-34062068

RESUMEN

Lithium is used in the treatment of bipolar disorder. We previously demonstrated that two types of transporters mediate the tubular reabsorption of lithium in rats, and suggested that sodium-dependent phosphate transporters play a role in lithium reabsorption with high affinity. In the present study, we examined sex differences in lithium reabsorption in rats. When lithium chloride was infused at 60 µg/min, creatinine clearance and the renal clearance of lithium were lower, and the plasma concentration of lithium was higher in female rats. These values reflected the higher fractional reabsorption of lithium in female rats. In rats infused with lithium chloride at 6 µg/min, the pharmacokinetic parameters of lithium examined were all similar in both sexes. The fractional reabsorption of lithium was decreased by foscarnet, a representative inhibitor of sodium-dependent phosphate transporters, in male and female rats when lithium chloride was infused at the low rate. Among the candidate transporters mediating lithium reabsorption examined herein, the mRNA expression of only PiT2, a sodium-dependent phosphate transporter, exhibited sexual dimorphism. The present results demonstrated sex differences in the tubular reabsorption of lithium with low affinity in rats.


Asunto(s)
Túbulos Renales/metabolismo , Cloruro de Litio/metabolismo , Reabsorción Renal , Proteínas Cotransportadoras de Sodio-Fosfato/metabolismo , Animales , Femenino , Infusiones Intravenosas , Cloruro de Litio/administración & dosificación , Cloruro de Litio/farmacocinética , Masculino , Ratas Wistar , Caracteres Sexuales , Factores Sexuales , Proteínas Cotransportadoras de Sodio-Fosfato/genética
19.
J Am Soc Nephrol ; 32(9): 2125-2136, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34045316

RESUMEN

Magnesium is an essential cofactor in many cellular processes, and aberrations in magnesium homeostasis can have life-threatening consequences. The kidney plays a central role in maintaining serum magnesium within a narrow range (0.70-1.10 mmol/L). Along the proximal tubule and thick ascending limb, magnesium reabsorption occurs via paracellular pathways. Members of the claudin family form the magnesium pores in these segments, and also regulate magnesium reabsorption by adjusting the transepithelial voltage that drives it. Along the distal convoluted tubule transcellular reabsorption via heteromeric TRPM6/7 channels predominates, although paracellular reabsorption may also occur. In this segment, the NaCl cotransporter plays a critical role in determining transcellular magnesium reabsorption. Although the general machinery involved in renal magnesium reabsorption has been identified by studying genetic forms of magnesium imbalance, the mechanisms regulating it are poorly understood. This review discusses pathways of renal magnesium reabsorption by different segments of the nephron, emphasizing newer findings that provide insight into regulatory process, and outlining critical unanswered questions.


Asunto(s)
Magnesio/metabolismo , Reabsorción Renal/fisiología , Claudinas/fisiología , Humanos , Nefronas/fisiopatología , Proteínas Serina-Treonina Quinasas/fisiología , Canales Catiónicos TRPM/fisiología
20.
Yakugaku Zasshi ; 141(5): 695-703, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33952754

RESUMEN

Cellular transport systems for both essential and toxic trace elements remain elusive. In our studies on the transport systems for cadmium (Cd), we found that the cellular uptake of Cd is mediated by the transporter for manganese (Mn). We identified ZIP8 and ZIP14, members of the ZIP zinc (Zn) transporter family, as transporters having high affinities for both Cd and Mn. Notably, the uptake of Cd into rice root from soil is mediated by a transporter for Mn as well. We found that ZIP8 is highly expressed at the S3 segment of the kidney proximal tubule and can transport glomerulus-filtered Cd and Mn ions in the lumen into epithelial cells of the proximal tubule, suggesting that ZIP8 has an important role in the renal reabsorption of both toxic Cd and essential Mn. Mutations in ZIP8 and ZIP14 genes were found in humans having congenital disorders associated with the disturbed transport of Mn, although ZIP8 mutation causes whole-body Mn deficiency while ZIP14 mutation causes Mn accumulation in the brain. Mutations in ZnT10, a Zn transporter responsible for Mn excretion, also cause hyperaccumulation of Mn in the brain. Results of genome-wide association studies have indicated that ZIP8 SNPs are involved in a variety of common diseases. Thus, ZIP8, ZIP14, and ZnT10 play crucial roles in the transport of Mn and thereby control Mn- and Cd-related biological events in the body.


Asunto(s)
Cadmio/metabolismo , Cadmio/toxicidad , Proteínas Portadoras/fisiología , Manganeso/metabolismo , Manganeso/toxicidad , Animales , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/fisiología , Estudio de Asociación del Genoma Completo , Humanos , Túbulos Renales Proximales/metabolismo , Mutación , Oryza/metabolismo , Raíces de Plantas/metabolismo , Reabsorción Renal
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