醛固酮诱导TIF新机制：FOXO1/Rab7轴对miR-26a表达调控的研究

Tubulointerstitial fibrosis (TIF) is the major hallmark in the development and progression of chronic kidney disease (CKD) to end-stage renal disease. We previously found that aldosterone administration increased urinary exosomal miR-26a, whereas the level of miR-26 is decreased in the kidney compared with the control group. The up-regulated expression of connective tissue growth factor (CTGF）, Smad4 and Collagen Iα, which were closely related to the progression of kidney fibrosis, are the direct target genes of miR-26a. We have also previously reported that aldosterone increased the activation of the FOXO（Forkhead transcription factor，O subfamily）1/Rab7 axis in podocytes and Rab7 is known as one of the key molecules in the regulation of exosome secretion. Hence, we hypothesize that activation of FOXO1/Rab7 axis induces the increase of exosomal miR-26a secretion and the decrease of miR-26a level in the tubule, leading to the increased expression of CTGF, Smad4 and Collagen Iα, which is a new mechanism of TIF induced by aldosterone. This study will use cell culture and animal models to clarify the role of miR-26a in the pathogenesis of aldosterone-induced TIF, and to provide a new theoretical basis for prevention and treatment of CKD.

肾小管间质纤维化（TIF）是慢性肾脏病（CKD）进展为终末期肾病的共同途径。我们前期研究发现：醛固酮诱导的TIF模型中，尿液外泌体miR-26a含量增加，肾脏miR-26a水平下降。与纤维化密切相关的结缔组织生长因子（CTGF）、Smad4和Collagen Iα基因都是miR-26a调控的直接靶基因。另外，我们之前曾报道：醛固酮参与了足细胞FOXO1/Rab7轴的激活，而Rab7是调控外泌体分泌的关键分子之一。因此，我们提出假说：FOXO1/Rab7轴的激活导致肾小管外泌体miR-26a排泄增加，肾小管上皮细胞内miR-26a水平下降，进而导致CTGF、Smad4和Collagen Iα等多个基因表达增加，该变化是醛固酮诱导TIF发生的新机制。本研究拟通过体外细胞培养和模式动物，探讨miR-26a在醛固酮诱导TIF发生中的作用和机制，为CKD临床防治提供新的理论依据。

肾小管间质纤维化是慢性肾脏病（CKD）进展为终末期肾病的共同途径，尿毒症心肌病和肌肉萎缩是慢性肾脏病的常见并发症。我们的研究发现：Ang-II诱导的肾损伤模型中，小鼠肾脏miR-26a显著下调，外源性给予miR-26a干预可以通过调控CTGF、Smad4和Collagen Iα等纤维化相关基因显著改善小鼠肾脏纤维化。同时我们发现，MSTP修饰的外泌体对CKD时损伤的心脏具有靶向性，而其携带miR-26a对尿毒症心肌病和肌肉萎缩具有显著的治疗效果。在此基础上，我们进一步探究了CKD背景下，巨噬细胞和心肌细胞的交互，发现了UCM中浸润的巨噬细胞通过分泌富含miR-155的外泌体直接靶向FOXO3a并促进心肌细胞焦亡。本研究通过体外细胞培养和模式动物，探讨CKD及其并发症的发病机制，并结合我们的研究结果，对治疗进行了探索，为CKD临床防治提供新的理论依据。