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

晚期糖基化终产物诱导MC中BMP 4-Smad 1信号通路下游软骨细胞标志蛋白的表达。此外，缺氧还诱导HIF-1和软骨细胞标志物的表达。SOX 9的过表达引起软骨细胞标志物的异位表达。观察糖尿病肾病小鼠肾小球中HIF-1、BMP 4和软骨细胞标志物的表达。SOX 9与HIF-1在糖尿病肾小球中共定位。BMP-4基因敲入转基因小鼠不仅表现出与DN相似的病理学改变，而且在软骨病变中诱导出软骨细胞标志物。HIF-1和BMP-4诱导SOX 9表达和随后的DN软骨形成表型改变。结果提示，慢性低氧应激下MC向软骨样细胞的转分化可能导致DN发生不可逆的结构改变。

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.