Department of Molecular Medicine Graduate School of Pharmaceutical Sciences, Kumamoto, Japan.
Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto, Japan.
Ren Fail. 2021 Dec;43(1):510-519. doi: 10.1080/0886022X.2021.1896548.
Alport syndrome (AS) is a hereditary glomerular nephritis caused by mutation in one of the type IV collagen genes α3/α4/α5 that encode the heterotrimer COL4A3/4/5. Failure to form a heterotrimer due to mutation leads to the dysfunction of the glomerular basement membrane, and end-stage renal disease. Previous reports have suggested the involvement of the receptor tyrosine kinase discoidin domain receptor (DDR) 1 in the progression of AS pathology. However, due to the similarity between DDR1 and DDR2, the role of DDR2 in AS pathology is unclear. Here, we investigated the involvement of DDR2 in AS using the X-linked AS mouse model. Mice were treated subcutaneously with saline or antisense oligonucleotide (ASO; 5 mg/kg or 15 mg/kg per week) for 8 weeks. Renal function parameters and renal histology were analyzed, and the gene expressions of inflammatory cytokines were determined in renal tissues. The expression level of DDR2 was highly elevated in kidney tissues of AS mice. Knockdown of using -specific ASO decreased the expression. However, the DDR2 ASO treatment did not improve the proteinuria or decrease the BUN level. DDR2 ASO also did not significantly ameliorate the renal injury, inflammation and fibrosis in AS mice. These results showed that knockdown by ASO had no notable effect on the progression of AS indicating that DDR2 may not be critically involved in AS pathology. This finding may provide useful information and further understanding of the role of DDRs in AS.
Alport 综合征（AS）是一种遗传性肾小球肾炎，由编码异三聚体 COL4A3/4/5 的 IV 型胶原基因 α3/α4/α5 中的突变引起。由于突变导致异三聚体无法形成，从而导致肾小球基底膜功能障碍和终末期肾病。先前的报告表明，受体酪氨酸激酶 discoidin 结构域受体（DDR）1 参与了 AS 病理的进展。然而，由于 DDR1 和 DDR2 之间的相似性，DDR2 在 AS 病理中的作用尚不清楚。在这里，我们使用 X 连锁 AS 小鼠模型研究了 DDR2 在 AS 中的参与情况。小鼠接受皮下注射生理盐水或反义寡核苷酸（ASO；每周 5mg/kg 或 15mg/kg）8 周。分析肾功能参数和肾脏组织学，并测定肾脏组织中炎症细胞因子的基因表达。AS 小鼠肾脏组织中 DDR2 的表达水平高度升高。使用 DDR2 特异性 ASO 敲低 表达。然而，DDR2 ASO 治疗并未改善蛋白尿或降低 BUN 水平。DDR2 ASO 也未显著改善 AS 小鼠的肾脏损伤、炎症和纤维化。这些结果表明，ASO 敲低对 AS 的进展没有明显影响，表明 DDR2 可能在 AS 病理中没有关键作用。这一发现可能为 DDR 在 AS 中的作用提供有用的信息和进一步的理解。
