Molecular mechanisms for irreversible phenotypic changes leading to renal failure in chronic kidney diseases.

晚期糖基化终产物诱导MCs中BMP4-Smad1信号通路下游的软骨细胞标记蛋白的表达。此外，低氧还可诱导HIF-1和软骨细胞标志物的表达。SOX9的过表达导致软骨细胞标志物的异位表达。观察糖尿病肾病小鼠肾小球HIF-1、BMP4和软骨细胞标志物的表达。在糖尿病肾小球中，SOX9与HIF-1共定位。BMP4基因敲入转基因小鼠不仅表现出与糖尿病肾病相似的病理损害，而且在硬化性病变中诱导出软骨细胞标志物。HIF-1和BMP4诱导SOX9表达和随后的糖尿病肾病软骨细胞表型改变。提示在慢性低氧应激条件下，肾小球系膜细胞向软骨细胞样细胞的转分化可能导致糖尿病肾病不可逆的结构改变。

Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of HIF-1, and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of chondrocyte markers. Glomerular expressions of HIF-1, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. SOX9 was colocalized with HIF-1 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. HIF-1 and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.