Department of Medicine, Johannes Gutenberg University, Mainz, Germany.
Mod Pathol. 2011 Aug;24(8):1101-10. doi: 10.1038/modpathol.2011.58. Epub 2011 Apr 15.
Podocin is a critical component of the glomerular filtration barrier, its mutations causing recessive steroid-resistant nephrotic syndrome. A GenBank analysis of the human podocin (NPHS2) gene resulted in the possible existence of a new splice variant of podocin in the kidney, missing the in-frame of exon 5, encoding the prohibitin homology domain. Using RT-polymerase chain reaction and immunoblotting followed by sequence analysis, we are for the first time able to prove the expression of a novel podocin isoform (isoform 2), exclusively and constitutively expressed in human podocytes. Furthermore, we reveal singular extrarenal podocin expression in human and murine testis. Our data show the Sertoli cells of the seminiferous tubules to be the origin of testicular podocin. Confocal laser microscopy illustrates the co-localization of podocin with filamentous actin within Sertoli cells, suggesting a role of podocin in the blood/testis barrier. These results led to the rationale to examine podocin expression in testes of men with Sertoli cell-only syndrome, a disorder characterized by azoospermia. Interestingly, we observed a complete down-regulation of podocin mRNA in Sertoli cell-only syndrome, indicating a possible role of podocin in the pathogenesis of this germinal aplasia. Men with Sertoli cell-only syndrome show normal renal podocin expression, suggesting an alternate regulation of the testicular promoter. Our findings may change the perception of podocin and give new insights into the ultrastructure of glomerular slit diaphragm and the blood/testis barrier.
足细胞是肾小球滤过屏障的关键组成部分，其突变导致常染色体隐性遗传的类固醇抵抗性肾病综合征。对人类足细胞蛋白（NPHS2）基因的 GenBank 分析提示，肾脏中可能存在足细胞的新剪接变异体，缺失编码抑制素同源结构域的外显子 5 框内序列。通过 RT-聚合酶链反应和免疫印迹分析，我们首次能够证明一种新型足细胞同工型（同工型 2）的表达，该同工型仅在人足细胞中持续表达。此外，我们还揭示了人类和鼠睾丸中存在独特的肾外足细胞表达。我们的数据表明，生精小管的 Sertoli 细胞是睾丸足细胞的起源。共聚焦激光显微镜显示足细胞与 Sertoli 细胞内的丝状肌动蛋白共定位，提示足细胞在血睾屏障中发挥作用。这些结果促使我们检查 Sertoli 细胞仅综合征患者睾丸中足细胞的表达，Sertoli 细胞仅综合征是一种以无精子症为特征的疾病。有趣的是，我们观察到 Sertoli 细胞仅综合征中足细胞 mRNA 的完全下调，表明足细胞在这种生殖发育不全的发病机制中可能发挥作用。Sertoli 细胞仅综合征患者的肾脏足细胞表达正常，提示睾丸启动子可能存在替代调节。我们的发现可能改变对足细胞的认识，并为肾小球裂孔隔膜和血睾屏障的超微结构提供新的见解。
