Immunology and Inflammation Center, Feinstein Institute for Medical Research and Zucker School of Medicine at Hofstra-Northwell, New York, USA.
Ochsner Clinic, New Orleans, USA.
Sci Rep. 2019 Mar 5;9(1):3582. doi: 10.1038/s41598-019-39376-y.
APOL1-miR193a axis participates in the preservation of molecular phenotype of differentiated podocytes (DPDs). We examined the hypothesis that APOL1 (G0) preserves, but APOL1 risk alleles (G1 and G2) disrupt APOL1-miR193a axis in DPDs. DPDG0s displayed down-regulation of miR193a, but upregulation of nephrin expression. DPDG1s/G2s exhibited an increase in miR193a and down-regulation of the expression of adherens complex's constituents (CD2AP, nephrin, and dendrin). DPDG0s showed decreased Cathepsin L, enhanced dynamin expressions, and the intact actin cytoskeleton. On the contrary, DPDG1s/G2s displayed an increase in Cathepsin L, but down-regulation of dynamin expressions and disorganization of the actin cytoskeleton. APOL1 silencing enhanced miR193a and Cathepsin L, but down-regulated dynamin expressions. DPDG1s/G2s displayed nuclear import of dendrin, indicating an occurrence of destabilization of adherens complexes in APOL1 risk milieu. These findings suggest that DPDG1s and DPDG2s developed disorganized actin cytoskeleton as a consequence of disrupted APOL1-miR193a axis. Interestingly, docking and co-labeling studies suggested an interaction between APOL1 and CD2AP. APOL1 and APOL1 transgenic mice displayed nuclear import of dendrin indicating destabilization of adherens complexes in podocytes; moreover, these mice showed a four-fold increase in urinary albumin to creatinine ratio and development of focal segmental glomerular lesions.
APOL1-miR193a 轴参与分化足细胞（DPD）分子表型的维持。我们检验了这样一个假设，即 APOL1（G0）保留，而 APOL1 风险等位基因（G1 和 G2）破坏了 DPD 中的 APOL1-miR193a 轴。DPDG0 显示 miR193a 下调，但肾素表达上调。DPDG1s/G2s 表现出 miR193a 增加和黏附复合物成分（CD2AP、肾素和 dendrin）表达下调。DPDG0 显示组织蛋白酶 L 减少，动力蛋白表达增强，肌动蛋白细胞骨架完整。相反，DPDG1s/G2s 显示组织蛋白酶 L 增加，但动力蛋白表达下调和肌动蛋白细胞骨架紊乱。APOL1 沉默增强了 miR193a 和组织蛋白酶 L，但下调了 dynamin 表达。DPDG1s/G2s 显示 dendrin 的核内输入，表明黏附复合物在 APOL1 风险环境中发生不稳定。这些发现表明，DPDG1s 和 DPDG2s 由于 APOL1-miR193a 轴的破坏而出现了紊乱的肌动蛋白细胞骨架。有趣的是，对接和共标记研究表明 APOL1 与 CD2AP 之间存在相互作用。APOL1 和 APOL1 转基因小鼠显示 dendrin 的核内输入，表明足细胞黏附复合物的不稳定；此外，这些小鼠的尿白蛋白/肌酐比值增加了四倍，并出现局灶节段性肾小球病变。
