Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Department of Nephrology, the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
J Hypertens. 2019 Oct;37(10):2061-2073. doi: 10.1097/HJH.0000000000002129.
Renovascular disease (RVD) produces chronic underperfusion of the renal parenchyma and progressive ischemic injury. Metabolic abnormalities often accompany renal ischemia, and are linked to poorer renal outcomes. However, the mechanisms of injury in kidneys exposed to the ischemic and metabolic components of RVD are incompletely understood. We hypothesized that coexisting renal artery stenosis (RAS) and metabolic syndrome (MetS) would exacerbate mitochondrial damage, aggravating poststenotic kidney injury in swine.
Domestic pigs were studied after 16 weeks of either standard diet (Lean) or high-fat/high-fructose (MetS) with or without superimposed RAS (n = 6 each). Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector-CT, and renal tubular mitochondrial structure, homeostasis and function and renal injury ex vivo.
Both RAS groups achieved significant stenosis. Single-kidney RBF and GFR were higher in MetS compared with Lean, but decreased in Lean+RAS and MetS+RAS vs. their respective controls. MetS and RAS further induced changes in mitochondrial structure, dynamics, and function, and their interaction (diet × ischemia) decreased matrix density, mitophagy, and ATP production, and lead to greater renal fibrosis.
Coexisting RAS and MetS synergistically aggravate mitochondrial structural damage and dysfunction, which may contribute to structural injury and dysfunction in the poststenotic kidney. These observations suggest that mitochondrial damage precedes loss of renal function in experimental RVD, and position mitochondria as novel therapeutic targets in these patients.
肾血管疾病（RVD）会导致肾实质慢性灌注不足和进行性缺血性损伤。代谢异常常伴随肾缺血发生，并与较差的肾脏预后相关。然而，暴露于 RVD 的缺血和代谢成分的肾脏损伤机制尚不完全清楚。我们假设并存的肾动脉狭窄（RAS）和代谢综合征（MetS）会加剧线粒体损伤，从而加重猪后狭窄肾脏损伤。
在标准饮食（Lean）或高脂肪/高果糖（MetS）喂养 16 周后，研究了家猪，其中或同时存在 RAS（每组各 6 只）。多探测器 CT 用于在体评估单肾肾血流（RBF）和肾小球滤过率（GFR），并在体评估肾小管线粒体结构、稳态和功能以及肾脏损伤。
两组 RAS 均达到显著狭窄。与 Lean 相比，MetS 组的单肾 RBF 和 GFR 更高，但在 Lean+RAS 和 MetS+RAS 组与各自对照组相比降低。MetS 和 RAS 进一步诱导了线粒体结构、动力学和功能的变化，其相互作用（饮食×缺血）降低了基质密度、线粒体自噬和 ATP 产生，并导致更大的肾脏纤维化。
并存的 RAS 和 MetS 协同加剧了线粒体结构损伤和功能障碍，这可能导致后狭窄肾脏的结构损伤和功能障碍。这些观察结果表明，线粒体损伤先于实验性 RVD 中肾功能丧失，将线粒体定位为这些患者的新的治疗靶点。
