COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.

中文翻译：

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牛磺熊去氧胆酸改善 COL4A3 突变引起的肾损伤


COL4A3/A4/A5 突变已被确定为奥尔波特综合征和其他遗传性慢性肾脏疾病的关键原因。然而，潜在的发病机制仍不清楚，也缺乏具体的治疗方法。在这里，我们通过将先前从一个大型阿尔波特综合征家族中鉴定出的突变（Col4a3 p.G799R）生成到小鼠体内，构建了转基因阿尔波特综合征小鼠模型。我们观察到该突变导致细胞内和分泌的 IV 型胶原 α3α4α5 异三聚体病理性减少。突变的IV型胶原α3链在内质网中异常积累并表现出分泌缺陷，导致体内和体外持续的内质网应激。 RNA-seq 分析表明 MyD88/p38 MAPK 通路在介导随后的炎症和凋亡信号激活中发挥关键作用。牛磺熊去氧胆酸是一种具有内质网应激抑制剂功能的化学伴侣药物，可有效抑制内质网应激，促进α3链的分泌，并抑制MyD88/p38 MAPK通路的激活。牛磺熊去氧胆酸治疗显着改善体内肾功能。这些结果部分阐明了与Alport综合征相关的肾损伤（尤其是肾小球损伤）的发病机制，并表明牛磺熊去氧胆酸可能有助于Alport综合征的早期临床治疗。