Trachtman H, Futterweit S, Singhal P C, Franki N, Sharma M, Sharma R, Savin V
Department of Pediatrics, Schneider Children's Hospital, New Hyde Park, NY 11040-1432, USA.
J Investig Med. 1999 Mar;47(3):114-20.
Primary focal segmental glomerulosclerosis (FSGS) recurs in nearly 30% of patients who progress to end-stage renal disease and then receive a kidney transplant. A circulating plasma factor has been isolated from these patients that increases glomerular permeability to albumin in vitro. Because of the pivotal role of the mesangial cell in the accumulation of extracellular matrix (ECM) material within the glomerulus and the modulation of matrix protein synthesis by nitric oxide (NO), we examined the effect of the FSGS factor on inducible nitric oxide synthase (iNOS) expression and NO production by cultured rat mesangial cells (RMC).
RMC were incubated with the supernatant following 70% ammonium sulfate precipitation of serum from patients with recurrent FSGS.
Addition of the FSGS factor to cultured RMC led to a significant inhibition of nitrite accumulation, an index of NO synthesis. There was a parallel decline in iNOS gene and protein expression. Sera obtained from control patients or those with minimal change nephrotic syndrome or diabetic nephropathy that was processed in the same manner as FSGS samples had no effect NO synthesis or iNOS activity. The inhibitory effect of the FSGS factor on NO production persisted despite addition of indomethacin (0.1-1 mumol/L) or cyclosporine (25 micrograms/mL) to test media.
These data indicate that the FSGS factor independently alters two aspects of glomerular function--permselectivity and matrix protein synthesis--by distinct mechanisms. FSGS factor-induced disturbances in iNOS gene and protein expression and NO production by mesangial cells may antagonize the antifibrotic effect of NO within the mesangium and contribute to progressive glomerulosclerosis in patients with primary FSGS.
原发性局灶节段性肾小球硬化（FSGS）在近30%进展至终末期肾病并接受肾移植的患者中复发。已从这些患者中分离出一种循环血浆因子，该因子在体外可增加肾小球对白蛋白的通透性。由于系膜细胞在肾小球内细胞外基质（ECM）物质积聚以及一氧化氮（NO）对基质蛋白合成的调节中起关键作用，我们研究了FSGS因子对培养的大鼠系膜细胞（RMC）诱导型一氧化氮合酶（iNOS）表达和NO产生的影响。
将复发性FSGS患者血清经70%硫酸铵沉淀后的上清液与RMC共同孵育。
向培养的RMC中添加FSGS因子导致亚硝酸盐积累显著抑制，亚硝酸盐积累是NO合成的一个指标。iNOS基因和蛋白表达呈平行下降。以与FSGS样本相同方式处理的对照患者或微小病变肾病或糖尿病肾病患者的血清对NO合成或iNOS活性无影响。尽管在测试培养基中添加了吲哚美辛（0.1 - 1 μmol/L）或环孢素（25 μg/mL），FSGS因子对NO产生的抑制作用仍然存在。
这些数据表明，FSGS因子通过不同机制独立改变肾小球功能的两个方面——滤过选择性和基质蛋白合成。FSGS因子诱导的系膜细胞iNOS基因和蛋白表达及NO产生的紊乱可能拮抗系膜内NO的抗纤维化作用，并导致原发性FSGS患者的进行性肾小球硬化。
