Urinary plasminogen/plasmin, or plasmin (ogen) uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin (ogen) as a “second hit” in kidney disease progression has yet to have been demonstrated in vivo. Additionally, association between plasmin (ogen) uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, an inhibitor of plasminogen activation, and measured changes in plasmin (ogen) uria. In a glomerular disease biorepository cohort (n = 128), we measured time‐of‐biopsy albuminuria, proteinuria, and plasmin (ogen) uria for correlations with kidney outcomes. In cultured human podocytes, plasminogen treatment was associated with decreased focal adhesion marker expression with rescue by amiloride. Increased glomerular plasmin (ogen) was found in PAN rats and focal segmental glomerulosclerosis (FSGS) patients. PAN nephropathy was associated with increases in plasmin (ogen) uria and proteinuria. Amiloride was protective against PAN‐induced glomerular injury, reducing CD36 scavenger receptor expression and oxidative stress. In patients, we found associations between plasmin (ogen) uria and edema status as well as eGFR. Our study demonstrates a role for plasmin (ogen)‐induced podocyte injury in the PAN nephropathy model, with amiloride having podocyte‐protective properties. In one of the largest glomerular disease cohorts to study plasminogen, we validated previous findings while suggesting a potentially novel relationship between plasmin (ogen) uria and estimated glomerular filtration rate (eGFR). Together, these findings suggest a role for plasmin (ogen) in mediating glomerular injury and as a viable targetable biomarker for podocyte‐sparing treatments.

中文翻译：

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纤溶酶原尿症与偶发性肾小球疾病中的足细胞损伤、水肿和肾功能不全有关

尿纤溶酶原/纤溶酶，或纤溶酶（原）尿，已在蛋白尿患者中得到证实，培养的足细胞暴露于纤溶酶原会通过氧化应激途径导致损伤。纤溶酶（原）作为肾脏疾病进展的“第二次打击”的致病作用尚未在体内得到证实。此外，纤溶酶（原）尿与肾小球疾病中肾功能之间的关联仍不清楚。我们在用纤溶酶原激活抑制剂阿米洛利治疗的嘌呤霉素氨基核苷 (PAN) 肾病大鼠模型中进行了比较研究，并测量了纤溶酶 (原) 尿的变化。在肾小球疾病生物样本库队列（n = 128）中，我们测量了活检时间白蛋白尿、蛋白尿和纤溶酶（原）尿与肾脏结局的相关性。在培养的人足细胞中，纤溶酶原治疗与阿米洛利拯救后粘着斑标志物表达降低有关。在 PAN 大鼠和局灶节段性肾小球硬化 (FSGS) 患者中发现肾小球纤溶酶 (原) 增加。PAN 肾病与纤溶酶（原）尿和蛋白尿的增加有关。阿米洛利对 PAN 诱导的肾小球损伤具有保护作用，可降低 CD36 清道夫受体表达和氧化应激。在患者中，我们发现纤溶酶（原）尿与水肿状态以及 eGFR 之间存在关联。我们的研究证明了纤溶酶（原）诱导的足细胞损伤在 PAN 肾病模型中的作用，阿米洛利具有足细胞保护特性。在研究纤溶酶原的最大肾小球疾病队列之一中，我们验证了先前的研究结果，同时提出了纤溶酶（原）尿和估计的肾小球滤过率（eGFR）之间的潜在新关系。总之，这些发现表明纤溶酶（原）在介导肾小球损伤中的作用，以及作为足细胞保留治疗的可行靶向生物标志物。