Significance of the urokinase-type plasminogen activator and its receptor in the progression of focal segmental glomerulosclerosis in clinical and mouse models

Abstract

BackgroundsuPAR biomarker generally considered a pathogenic factor in FSGS. However, studies have been published that dispute this conclusion. The current study was designed to investigate the roles of uPA and suPAR in FSGS in clinical and mouse models.MethodsClinical subjects including those with biopsy-proven FSGS and MCD were enrolled. To verify the role of uPA in FSGS, Adriamycin was used to induce FSGS in uPA knockout (uPA−/−) and BALB/c (WT) mice. Proteinuria and suPAR, the cleaved/intact forms of the circulating suPAR, and possible proteases involving cleavage of the suPAR were also studied.ResultsFSGS clinical cases presented significantly higher serum levels of suPAR and Cr and lower serum levels of uPA. In the mice model, the uPA−/− group exhibited faster disease progression and worsening proteinuria than the WT group. In addition, the uPA−/− group had higher plasma suPAR levels, glomerular cell apoptosis, and dysregulation of the Th1/Th2 balance. In an analysis of suPAR variants in FSGS, both the intact and cleaved forms of the suPAR were higher in clinical subjects and the mouse model. However, the process of suPAR cleavage was not mediated by enzymatic activities of the uPA, elastase, or cathepsin G.ConclusionsA deficiency of uPA accelerated the progression of Adriamycin-induced mouse FSGS model. Decrease of serum uPA levels may be an indicator of the progression of FSGS in clinical subjects and animal models.

Serum soluble urokinase type plasminogen activated receptor and focal segmental glomerulosclerosis: a systematic review and meta-analysis

“…Thus, 364 studies were initially included, among which 306 studies were excluded after reading the title and abstract. After reading the full text, another 29 studies were excluded; therefore, 29 studies were finally included 9–11 21–46. A flow chart of the study selection process is presented in figure 1.…”

“…In a total of 19 studies,9 22 24–28 30 31 33–35 37 38 40 42 44–46 the concentrations of suPAR in primary FSGS and MCD were compared, and the results showed that the concentration of suPAR in primary FSGS was significantly higher compared with that in MCD (p<0.001; SMD: 1.72; 95% CI 1.17 to 2.28; I 2 =94.0%) (table 2).…”

Functions of Urokinase and Its Receptor in Pathological Tissues of Patients with Gastric Cancer

“…Уровень uPAR в здоровом организме вполне стабилен, но при раке повышается, т. к. uPAR конкурирует с uPA за участие во многих непротеолитических биологических процессах, таких как миграция, адгезия и пролиферация клеток, ангиогенез [22].…”

“…Несмотря на то что экспрессия системы uPA наблюдается как на раковых клетках, так и на поддерживающей строме, на опухолевых клетках она выше, что и объясняет их биологическую агрессивность, эти показатели весьма актуальны для прогностических результатов [20][21][22]. Система uPA является важным прогностическим маркером при различных онкологических заболеваниях, ее определение уже рекомендуют к включению в рутинную клиническую практику [11], однако этот вопрос не исследовался при перитонеальном распространении рака желудка.…”

The natural compound 2,3,5,4′‐tetrahydroxystilbene‐2‐O‐β‐d glucoside protects against adriamycin‐induced nephropathy through activating the Nrf2‐Keap1 antioxidant pathway

“…After arrival, 6‐week‐old female Balb/c mice (LASCO, Taipei, Taiwan) were randomly allocated to groups of four in macrolon II cages. Experimental FSGS was induced by intravenous administration of AD (Selleckchem, Houston, TX) at a dose of 10 mg/kg as previously described . This study was approved by the Animal Experimentation Ethical Committee of Taipei Medical University.…”