Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China.
Affiliated Drum Tower Hospital of Nanjing University, Nanjing Jiangsu, China.
Oxid Med Cell Longev. 2022 Mar 20;2022:2453617. doi: 10.1155/2022/2453617. eCollection 2022.
Mitochondrial damage contributes to extracellular matrix (ECM) deposition and renal fibrosis. In this study, we aimed (1) to investigate whether fluorofenidone (AKF-PD) can attenuate mitochondrial damage in two renal fibrosis models: unilateral ureteral obstruction (UUO) and renal ischemia-reperfusion injury (IRI), and (2) to explore the underlying mechanism.
Mitochondrial damage and renal lesions were analyzed in the UUO and IRI models. Mitochondrial energy metabolism, mitochondrial biogenesis, and oxidative stress were measured to assess the effect of AKF-PD on mitochondrial damage and to explore the underlying mechanism. In addition, HK-2 cells were stimulated with TGF- with and without AKF-PD. The mitochondrial morphology, mtROS, ATP contents, and redox-related proteins were then examined.
In both UUO and IRI models, AKF-PD relieved renal fibrosis, maintained mitochondrial structure, and increased mitochondrial DNA copy numbers. The protection was associated with (1) sustaining mitochondrial energy metabolism, evident by elevations of tricarboxylic acid (TCA) cycle enzymes and mitochondrial respiratory chain complexes; (2) improving mitochondrial biogenesis with increases of TFAM, NRF1, PGC-1, and SIRT1; and (3) reducing mitochondrial oxidative stress likely via regulating SOD2, SIRT3, and NOX4 expressions. In HK-2 cells treated with TGF-, AKF-PD protected mitochondria along with improving mitochondrial morphology, enhancing ATP production, reducing mtROS, and regulating SOD2, SIRT3, and NOX4 expression.
We demonstrate that AKF-PD inhibited renal fibrosis at least in part via protecting mitochondria from damages developed in the UUO and IRI models. The mitochondrial protection was associated with sustaining mitochondrial energy metabolism, improving mitochondrial biogenesis, and reducing mitochondrial oxidative stress. This research verified the protective effect of AKF-PD on mitochondria in the UUO and IRI models and elaborated the underlying mechanism.
线粒体损伤导致细胞外基质（ECM）沉积和肾纤维化。本研究旨在：（1）研究氟芬尼酮（AKF-PD）是否能减轻单侧输尿管梗阻（UUO）和肾缺血再灌注损伤（IRI）两种肾纤维化模型中的线粒体损伤；（2）探讨其作用机制。
分析 UUO 和 IRI 模型中的线粒体损伤和肾脏病变。通过测定线粒体能量代谢、线粒体生物发生和氧化应激来评估 AKF-PD 对线粒体损伤的影响，并探讨其作用机制。此外，用 TGF-β刺激 HK-2 细胞，同时给予和不给予 AKF-PD，然后检测线粒体形态、mtROS、ATP 含量和氧化还原相关蛋白。
在 UUO 和 IRI 模型中，AKF-PD 均能缓解肾纤维化，维持线粒体结构，增加线粒体 DNA 拷贝数。保护作用与（1）维持三羧酸（TCA）循环酶和线粒体呼吸链复合物升高的线粒体能量代谢有关；（2）通过上调 TFAM、NRF1、PGC-1 和 SIRT1 改善线粒体生物发生；（3）可能通过调节 SOD2、SIRT3 和 NOX4 表达来减少线粒体氧化应激有关。在 TGF-β处理的 HK-2 细胞中，AKF-PD 保护线粒体，改善线粒体形态，增强 ATP 生成，减少 mtROS，调节 SOD2、SIRT3 和 NOX4 的表达。
我们证明 AKF-PD 通过抑制 UUO 和 IRI 模型中发生的线粒体损伤来抑制肾纤维化，至少部分是通过保护线粒体。线粒体保护与维持线粒体能量代谢、改善线粒体生物发生和减少线粒体氧化应激有关。这项研究验证了 AKF-PD 在 UUO 和 IRI 模型中对线粒体的保护作用，并阐述了其作用机制。
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