Oxlund Christina, Kurt Birgül, Schwarzensteiner Ilona, Hansen Mie R, Stæhr Mette, Svenningsen Per, Jacobsen Ib A, Hansen Pernille B, Thuesen Anne D, Toft Anja, Hinrichs Gitte R, Bistrup Claus, Jensen Boye L
Research Unit for Cardiovascular and Metabolic Prevention, Department of Endocrinology, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense C, Denmark.
Institute of Physiology, University of Regensburg, Regensburg, Germany.
Pflugers Arch. 2017 Jun;469(5-6):655-667. doi: 10.1007/s00424-017-1938-6. Epub 2017 Feb 24.
The proteinase prostasin is a candidate mediator for aldosterone-driven proteolytic activation of the epithelial sodium channel (ENaC). It was hypothesized that the aldosterone-mineralocorticoid receptor (MR) pathway stimulates prostasin abundance in kidney and urine. Prostasin was measured in plasma and urine from type 2 diabetic patients with resistant hypertension (n = 112) randomized to spironolactone/placebo in a clinical trial. Prostasin protein level was assessed by immunoblotting in (1) human and rat urines with/without nephrotic syndrome, (2) human nephrectomy tissue, (3) urine and kidney from aldosterone synthase-deficient (AS) mice and ANGII- and aldosterone-infused mice, and in (4) kidney from adrenalectomized rats. Serum aldosterone concentration related to prostasin concentration in urine but not in plasma. Plasma prostasin concentration increased significantly after spironolactone compared to control. Urinary prostasin and albumin related directly and were reduced by spironolactone. In patients with nephrotic syndrome, urinary prostasin protein was elevated compared to controls. In rat nephrosis, proteinuria coincided with increased urinary prostasin, unchanged kidney tissue prostasin, and decreased plasma prostasin while plasma aldosterone was suppressed. Prostasin protein abundance in human nephrectomy tissue was similar across gender and ANGII inhibition regimens. Prostasin urine abundance was not different in AS and aldosterone-infused mice. Prostasin kidney level was not different from control in adrenalectomized rats and AS mice. We found no evidence for a direct relationship between mineralocorticoid receptor signaling and kidney and urine prostasin abundance. The reduction of urinary prostasin in spironolactone-treated patients is most likely the result of an improved glomerular filtration barrier function and generally reduced proteinuria.
蛋白酶前列腺素原是醛固酮驱动的上皮钠通道（ENaC）蛋白水解激活的候选介质。据推测，醛固酮 - 盐皮质激素受体（MR）途径可刺激肾脏和尿液中前列腺素原的丰度。在一项临床试验中，对112例患有顽固性高血压的2型糖尿病患者随机给予螺内酯/安慰剂，检测其血浆和尿液中的前列腺素原。通过免疫印迹法评估前列腺素原蛋白水平，检测对象包括：（1）有/无肾病综合征的人尿和大鼠尿；（2）人肾切除组织；（3）醛固酮合酶缺陷（AS）小鼠以及输注血管紧张素II和醛固酮的小鼠的尿液和肾脏；（4）肾上腺切除大鼠的肾脏。血清醛固酮浓度与尿液中而非血浆中的前列腺素原浓度相关。与对照组相比，服用螺内酯后血浆前列腺素原浓度显著升高。尿中前列腺素原与白蛋白直接相关，且螺内酯可使其降低。肾病综合征患者的尿前列腺素原蛋白水平高于对照组。在大鼠肾病中，蛋白尿与尿前列腺素原增加、肾组织前列腺素原不变以及血浆前列腺素原降低同时出现，而血浆醛固酮受到抑制。人肾切除组织中前列腺素原蛋白丰度在不同性别和血管紧张素II抑制方案中相似。AS小鼠和输注醛固酮的小鼠尿中前列腺素原丰度无差异。肾上腺切除大鼠和AS小鼠的肾脏中前列腺素原水平与对照组无差异。我们没有发现盐皮质激素受体信号与肾脏和尿液中前列腺素原丰度之间存在直接关系的证据。螺内酯治疗患者尿中前列腺素原的降低很可能是肾小球滤过屏障功能改善和蛋白尿普遍减少的结果。
