Tubulointerstitial fibrosis plays an important role in the progression of diabetic kidney disease (DKD). Sacubitril/valsartan (Sac/Val) exerts a robust beneficial effect in DKD. However, the potential functional effect of Sac/Val on tubulointerstitial fibrosis in DKD is still largely unclear. Streptozotocin-induced diabetic mice were given Sac/Val or Val by intragastric administration once a day for 12 weeks. The renal function, the pathological changes of tubule injury and tubulointerstitial fibrosis, as well as mitochondrial morphology of renal tubules in mice, were evaluated. Genome-wide gene expression analysis was performed to identify the potential mechanisms. Meanwhile, human tubular epithelial cells (HK-2) were cultured in high glucose condition containing LBQ657/valsartan (LBQ/Val). Further, mitochondrial functions and Sirt1/PGC1α pathway of tubular epithelial cells were assessed by Western blot, Real-time-PCR, JC-1, MitoSOX or MitoTracker. Finally, the Sirt1 specific inhibitor, EX527, was used to explore the potential effects of Sirt1 signaling in vivo and in vitro. We found that Sac/Val significantly ameliorated the decline of renal function and tubulointerstitial fibrosis in DKD mice. The enrichment analysis of gene expression indicated metabolism as an important modulator in DKD mice with Sac/Val administration, in which mitochondrial homeostasis plays a pivotal role. Then, the decreased expression of Tfam and Cox IV;, as well as changes of mitochondrial function and morphology, demonstrated the disruption of mitochondrial homeostasis under DKD conditions. Interestingly, Sac/Val administration was found to restore mitochondrial homeostasis in DKD mice and in vitro model of HK-2 cells. Further, we demonstrated that Sirt1/PGC1α, a crucial pathway in mitochondrial homeostasis, was activated by Sac/Val both in vivo and in vitro. Finally, the beneficial effects of Sac/Val on mitochondrial homeostasis and tubulointerstitial fibrosis was partially abolished in the presence of Sirt1 specific inhibitor. Taken together, we demonstrate that Sac/Val ameliorates tubulointerstitial fibrosis by restoring Sirt1/PGC1α pathway-mediated mitochondrial homeostasis in DKD, providing a theoretical basis for delaying the progression of DKD in clinical practice.

中文翻译：

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沙库巴曲/缬沙坦通过恢复糖尿病肾病线粒体稳态来改善肾小管间质纤维化

肾小管间质纤维化在糖尿病肾病（DKD）的进展中起着重要作用。沙库巴曲/缬沙坦 (Sac/Val) 对 DKD 具有强大的有益作用。然而，Sac/Val 对 DKD 肾小管间质纤维化的潜在功能影响仍不清楚。链脲佐菌素诱导的糖尿病小鼠每天一次灌胃Sac/Val或Val，持续12周。评价小鼠肾功能、肾小管损伤、肾小管间质纤维化的病理变化以及肾小管线粒体形态。进行全基因组基因表达分析以确定潜在的机制。同时，在含有LBQ657/缬沙坦(LBQ/Val)的高葡萄糖条件下培养人肾小管上皮细胞(HK-2)。此外，通过Western blot、Real-time-PCR、JC-1、MitoSOX或MitoTracker评估肾小管上皮细胞的线粒体功能和Sirt1/PGC1α通路。最后，使用Sirt1特异性抑制剂EX527探索Sirt1信号传导在体内和体外的潜在影响。我们发现 Sac/Val 显着改善 DKD 小鼠肾功能下降和肾小管间质纤维化。基因表达的富集分析表明，代谢是 Sac/Val 给药 DKD 小鼠的重要调节剂，其中线粒体稳态发挥着关键作用。然后，Tfam 和 Cox IV 表达下降，以及线粒体功能和形态的变化，表明 DKD 条件下线粒体稳态被破坏。有趣的是，发现 Sac/Val 给药可以恢复 DKD 小鼠和 HK-2 细胞体外模型中的线粒体稳态。此外，我们证明了 Sirt1/PGC1α（线粒体稳态的关键途径）在体内和体外均被 Sac/Val 激活。最后，Sac/Val 对线粒体稳态和肾小管间质纤维化的有益作用在 Sirt1 特异性抑制剂的存在下被部分消除。综上所述，我们证明 Sac/Val 通过恢复 DKD 中 Sirt1/PGC1α 通路介导的线粒体稳态来改善肾小管间质纤维化，为临床实践中延缓 DKD 进展提供理论基础。