Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin analogs can delay the progression of DN, but the mechanism is not fully understood. In this study, we found that low molecular weight heparin therapy significantly upregulated some downstream proteins of the peroxisome proliferator–activated receptor (PPAR) signaling pathway by label-free quantification of the mouse kidney proteome. Through cell model verification, low molecular weight heparin can protect the heparan sulfate of renal tubular epithelial cells from being degraded by heparanase that is highly expressed in a high-glucose environment, enhance the endocytic recruitment of fatty acid–binding protein 1, a coactivator of the PPAR pathway, and then regulate the activation level of intracellular PPAR. In addition, we have elucidated for the first time the molecular mechanism of heparan sulfate and fatty acid–binding protein 1 interaction. These findings provide new insights into understanding the role of heparin in the pathogenesis of DN and developing corresponding treatments.

中文翻译：

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低分子肝素通过保护细胞糖萼促进PPAR通路延缓糖尿病肾病进展


糖尿病肾病（DN）是糖尿病患者最重要的合并症之一，是导致终末期肾病的主要因素。肝素类似物可以延缓 DN 的进展，但其机制尚不完全清楚。在这项研究中，我们通过对小鼠肾脏蛋白质组的无标记定量，发现低分子量肝素治疗显着上调过氧化物酶体增殖物激活受体（PPAR）信号通路的一些下游蛋白。通过细胞模型验证，低分子量肝素可以保护肾小管上皮细胞的硫酸乙酰肝素不被高糖环境下高表达的乙酰肝素酶降解，增强脂肪酸结合蛋白1（脂肪酸结合蛋白1的共激活剂）的内吞募集。 PPAR通路，进而调节细胞内PPAR的激活水平。此外，我们还首次阐明了硫酸乙酰肝素与脂肪酸结合蛋白1相互作用的分子机制。这些发现为了解肝素在 DN 发病机制中的作用和开发相应的治疗方法提供了新的见解。