Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
Department of the Thyroid and Breast Surgery, Xianyang Central Hospital, Xianyang 712000, China.
Biomolecules. 2024 Sep 29;14(10):1233. doi: 10.3390/biom14101233.
Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of L. and the leaves of L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against renal fibrosis and the underlying mechanisms are still poorly understood. Given that many actions of ISO could be similarly attained by hydrogen sulfide (HS), we speculated that ISO may work through the induction of endogenous HS. To test the hypothesis, we established the unilateral ureteral obstruction (UUO) renal fibrosis rat model and transforming growth factor-β1(TGF-β1)-induced fibrosis in cultured renal tubular cells. ISO treatment inhibited epithelial-mesenchymal transition (EMT) formation, decreased extracellular matrix (ECM) deposition, and relieved renal fibrosis. Further analysis revealed that ISO stimulated the expression of the HS-synthesizing enzyme cystathionine lyase (CSE) and cystathionine beta-synthase (CBS), and promoted HS production in vivo and in vitro. The elevated HS attenuated oxidative stress and elevated the thiol level. It induced Keap1 sulfhydration, disrupted Keap1-Nrf2 interaction, and promoted the entry of Nrf2 into the nucleus. Finally, we found that circulating HS mainly derived from the liver, and not the kidney. Collectively, our study revealed that ISO alleviated renal fibrosis by inducing endogenous HS and regulating Keap1-Nrf2 interaction through sulfhydration of Keap1. Endogenous HS could be an important mediator underlying the pharmacological actions of ISO. Due to the multifunctional properties of HS, the HS-inducing nature of ISO could be exploited to treat various diseases.
山奈酚（ISO）是一种主要从 和 的果实和叶子中分离出来的活性类黄酮化合物。先前的研究表明 ISO 在肝脏和肺部具有抗纤维化作用，尽管其对肾脏纤维化的潜在保护作用及其潜在机制仍知之甚少。鉴于 ISO 的许多作用可以通过硫化氢（HS）类似地实现，我们推测 ISO 可能通过诱导内源性 HS 起作用。为了验证这一假设，我们建立了单侧输尿管梗阻（UUO）肾纤维化大鼠模型和转化生长因子-β1（TGF-β1）诱导的肾小管细胞纤维化模型。ISO 治疗抑制了上皮-间充质转化（EMT）的形成，减少了细胞外基质（ECM）的沉积，并缓解了肾纤维化。进一步分析表明，ISO 刺激了 HS 合成酶胱硫醚γ裂解酶（CSE）和胱硫醚β合酶（CBS）的表达，促进了体内和体外 HS 的产生。升高的 HS 减轻了氧化应激并提高了巯基水平。它诱导 Keap1 硫醇化，破坏 Keap1-Nrf2 相互作用，并促进 Nrf2 进入细胞核。最后，我们发现循环 HS 主要来自肝脏，而不是肾脏。综上所述，我们的研究表明，ISO 通过诱导内源性 HS 并通过 Keap1 硫醇化调节 Keap1-Nrf2 相互作用来减轻肾脏纤维化。内源性 HS 可能是 ISO 药理作用的重要介导物。由于 HS 的多功能特性，ISO 的 HS 诱导特性可用于治疗各种疾病。
