Department of Nephrology and Endocrinology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Division of Genomic Medicine and Disease Prevention, Institute of Medical Science, The University of Tokyo, Shirokanedai, 4-6-1 Minato-ku, Tokyo, 108-8639, Japan.
Sci Rep. 2020 Dec 3;10(1):21103. doi: 10.1038/s41598-020-77952-9.
Chronic kidney disease is a public health burden and it remains unknown which genetic loci are associated with kidney function in the Japanese population, our genome-wide association study using the Biobank Japan dataset (excluding secondary kidney diseases, such as diabetes mellitus) clearly revealed that almost half of the top 50 single nucleotide polymorphisms associated with estimated glomerular filtration rate are located in the SHROOM3 gene, suggesting that SHROOM3 will be responsible for kidney function. Thus, to confirm this finding, supportive functional analyses were performed on Shroom3 in mice using fullerene-based siRNA delivery, which demonstrated that Shroom3 knockdown led to albuminuria and podocyte foot process effacement. The in vitro experiment shows that knockdown of Shroom3 caused defective formation of lamellipodia in podocyte, which would lead to the disruption of slit diaphragm. These results from the GWAS, in vivo and in vitro experiment were consistent with recent studies reporting that albuminuria leads to impairment of kidney function.
慢性肾脏病是一个公共卫生负担，目前尚不清楚哪些遗传位点与日本人的肾功能有关。我们使用日本生物银行数据集（不包括糖尿病等继发性肾脏疾病）进行的全基因组关联研究清楚地表明，与估算肾小球滤过率相关的前 50 个单核苷酸多态性中，几乎有一半位于 SHROOM3 基因中，表明 SHROOM3 将负责肾功能。因此，为了证实这一发现，我们使用富勒烯基 siRNA 递送来对小鼠中的 Shroom3 进行了支持性的功能分析，结果表明 Shroom3 的敲低导致白蛋白尿和足细胞足突融合。体外实验表明，Shroom3 的敲低导致足细胞中片状伪足的形成缺陷，从而导致裂孔隔膜的破坏。这些来自 GWAS、体内和体外实验的结果与最近的研究结果一致，即白蛋白尿导致肾功能受损。
