FK228调控HDAC1-Klotho-TGF-β1轴改善移植肾间质纤维化的作用机制研究

移植肾间质纤维化是慢性移植肾功能丧失的主要病理表现，也是影响移植肾长期存活的关键。组蛋白去乙酰化酶（HDACs）在肾间质纤维化中起着关键作用。在肾间质纤维化中，抗衰老蛋白Klotho表达下降，使TGF-β1信号通路激活。研究发现，HDAC1参与调控Klotho的表达，但其具体机制仍需进一步探讨。申请人前期发现特异性HDAC抑制剂FK228可有效缓解小鼠肾间质纤维化。因此，申请人提出FK228可以通过抑制HDAC1，上调Klotho基因表达，进而抑制TGF-β1信号通路，最终改善移植肾间质纤维化。本研究拟从大鼠移植肾间质纤维化模型和细胞培养两个层面探讨FK228调控HDAC1-Klotho-TGF-β1轴改善移植肾间质纤维化的机制，为提高移植肾的长期存活提供新思路。

Interstitial fibrosis of transplanted kidney is the main pathological manifestation of chronic renal failure and the key factor affecting the long-term survival of transplanted kidney. Histone deacetylases (HDACs) play a key role in renal interstitial fibrosis. The decreased expression of anti-aging protein Klotho in renal interstitial fibrosis activates the TGF-β1 signaling pathway. Studies have shown that HDAC1 is involved in regulating the expression of Klotho, but the specific mechanism still needs to be explored. The applicant previously found that the specific HDAC inhibitor FK228 could effectively alleviate renal interstitial fibrosis in mice. Therefore, the applicant proposed that FK228 could inhibit the expression of Klotho by inhibiting HDAC1, then inhibit the TGF-β1 signaling pathway, and finally alleviate the interstitial fibrosis of the transplanted kidney. This study aims to explore the mechanism of FK228 regulating the HDAC1-Klotho-TGF-β1 axis to improve the interstitial fibrosis of transplanted kidney from two levels of rat transplanted kidney fibrosis model and cell culture, so as to provide a new idea for improving the long-term survival of transplanted kidney.