Department of Cardiovascular and Renal Research, University of Southern Denmark , Odense , Denmark.
Odense University Hospital, Department of Nephrology , Odense , Denmark.
Am J Physiol Renal Physiol. 2018 Jul 1;315(1):F151-F160. doi: 10.1152/ajprenal.00545.2017. Epub 2018 Jan 24.
Albuminuria predicts adverse renal outcome in kidney transplant recipients. The present study addressed the hypothesis that albuminuria is associated with increased urine serine proteases with the ability to activate the epithelial sodium channel (ENaC) and with greater extracellular volume and higher blood pressure. In a cross-sectional design, kidney transplant recipients with ( n = 18) and without ( n = 19) albuminuria were included for office blood pressure measurements, estimation of volume status by bioimpedance, and collection of spot urine and plasma samples. Urine was analyzed for serine proteases and for the ability to activate ENaC current in vitro. Urine exosome protein was immunoblotted for prostasin and γ-ENaC protein. In the present study, it was found that, compared with nonalbuminuria (8.8 mg/g creatinine), albuminuric (1,722 mg/g creatinine) kidney transplant recipients had a higher systolic and diastolic blood pressure, despite receiving significantly more antihypertensives, and a greater urinary total plasminogen, active plasmin, active urokinase-type plasminogen activator, and prostasin protein abundance, which correlated significantly with u-albumin. Fluid overload correlated with systolic blood pressure, urinary albumin/creatinine, and plasminogen/creatinine. Urine from albuminuric kidney transplant recipients evoked a greater amiloride- and aprotinin-sensitive inward current in single collecting duct cells (murine cell line M1). γENaC subunits at 50 and 75 kDa showed increased abundance in urine exosomes from albuminuric kidney transplant recipients when compared with controls. These findings show that albuminuria in kidney transplant recipients is associated with hypertension, ability of urine to proteolytically activate ENaC current, and increased abundance of γENaC. ENaC activity could contribute to hypertension and adverse outcome in posttransplant proteinuria.
尿白蛋白预示着肾移植受者的不良肾脏结局。本研究旨在验证尿白蛋白与能够激活上皮钠通道（ENaC）的尿丝氨酸蛋白酶增多以及细胞外液容量增加和血压升高相关的假说。在一项横断面设计中，纳入了 18 例有尿白蛋白和 19 例无尿白蛋白的肾移植受者，以进行诊室血压测量、生物电阻抗法评估容量状态以及采集点尿和血浆样本。尿液用于分析丝氨酸蛋白酶和体外激活 ENaC 电流的能力。尿液外泌体蛋白用于检测前列腺素原和 γ-ENaC 蛋白。本研究发现，与无白蛋白尿（8.8mg/g 肌酐）相比，白蛋白尿（1722mg/g 肌酐）的肾移植受者尽管接受了更多的降压药物，但收缩压和舒张压仍较高，且尿总纤溶酶原、活性纤溶酶、活性尿激酶型纤溶酶原激活物和前列腺素原蛋白丰度较高，与 u-白蛋白显著相关。液体超负荷与收缩压、尿白蛋白/肌酐和纤溶酶原/肌酐相关。与对照组相比，白蛋白尿的肾移植受者的尿液在单个集合管细胞（鼠源细胞系 M1）中可引起更大的阿米洛利和抑肽酶敏感内向电流。与对照组相比，白蛋白尿的肾移植受者的尿液外泌体中 50 和 75kDa 的 γENaC 亚基丰度增加。这些发现表明，肾移植受者的白蛋白尿与高血压、尿液蛋白水解激活 ENaC 电流的能力以及 γENaC 丰度增加相关。ENaC 活性可能导致移植后蛋白尿患者的高血压和不良结局。
