Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43606, USA.
Department of Medicine, University of Alkafeel College of Medicine, Najaf 54001, Iraq.
Int J Mol Sci. 2023 Jun 13;24(12):10062. doi: 10.3390/ijms241210062.
Diet-induced models of chronic kidney disease (CKD) offer several advantages, including clinical relevance and animal welfare, compared with surgical models. Oxalate is a plant-based, terminal toxic metabolite that is eliminated by the kidneys through glomerular filtration and tubular secretion. An increased load of dietary oxalate leads to supersaturation, calcium oxalate crystal formation, renal tubular obstruction, and eventually CKD. Dahl-Salt-Sensitive (SS) rats are a common strain used to study hypertensive renal disease; however, the characterization of other diet-induced models on this background would allow for comparative studies of CKD within the same strain. In the present study, we hypothesized that SS rats on a low-salt, oxalate rich diet would have increased renal injury and serve as novel, clinically relevant and reproducible CKD rat models. Ten-week-old male SS rats were fed either 0.2% salt normal chow (SS-NC) or a 0.2% salt diet containing 0.67% sodium oxalate (SS-OX) for five weeks.Real-time PCR demonstrated an increased expression of inflammatory marker interleukin-6 (IL-6) ( < 0.0001) and fibrotic marker Timp-1 metalloproteinase ( < 0.0001) in the renal cortex of SS-OX rat kidneys compared with SS-NC. The immunohistochemistry of kidney tissue demonstrated an increase in CD-68 levels, a marker of macrophage infiltration in SS-OX rats ( < 0.001). In addition, SS-OX rats displayed increased 24 h urinary protein excretion (UPE) ( < 0.01) as well as significant elevations in plasma Cystatin C ( < 0.01). Furthermore, the oxalate diet induced hypertension ( < 0.05). A renin-angiotensin-aldosterone system (RAAS) profiling (via liquid chromatography-mass spectrometry; LC-MS) in the SS-OX plasma showed significant ( < 0.05) increases in multiple RAAS metabolites including angiotensin (1-5), angiotensin (1-7), and aldosterone. The oxalate diet induces significant renal inflammation, fibrosis, and renal dysfunction as well as RAAS activation and hypertension in SS rats compared with a normal chow diet. This study introduces a novel diet-induced model to study hypertension and CKD that is more clinically translatable and reproducible than the currently available models.
饮食诱导的慢性肾脏病（CKD）模型与手术模型相比，具有临床相关性和动物福利等优势。草酸是一种植物源性、终末毒性代谢物，通过肾小球滤过和肾小管分泌从肾脏中排出。饮食中草酸负荷增加会导致过饱和、草酸钙晶体形成、肾小管阻塞，最终导致 CKD。Dahl-Salt-Sensitive（SS）大鼠是一种常用的研究高血压肾病的品系；然而，在这种背景下对其他饮食诱导模型的特征描述将允许在同一品系内对 CKD 进行比较研究。在本研究中，我们假设低盐、富含草酸的饮食会导致 SS 大鼠的肾脏损伤增加，并成为新型、具有临床相关性和可重复的 CKD 大鼠模型。10 周龄雄性 SS 大鼠分别给予 0.2%盐正常饲料（SS-NC）或 0.2%盐含 0.67%草酸钠饲料（SS-OX）喂养 5 周。实时 PCR 显示，与 SS-NC 相比，SS-OX 大鼠肾脏皮质中炎症标志物白细胞介素 6（IL-6）（<0.0001）和纤维化标志物 TIMP-1 金属蛋白酶（<0.0001）的表达增加。肾组织免疫组化显示，SS-OX 大鼠 CD-68 水平升高，这是巨噬细胞浸润的标志物（<0.001）。此外，SS-OX 大鼠 24 小时尿蛋白排泄量（UPE）增加（<0.01），血浆胱抑素 C 水平显著升高（<0.01）。此外，草酸盐饮食可引起高血压（<0.05）。SS-OX 血浆中的肾素-血管紧张素-醛固酮系统（RAAS）分析（通过液相色谱-质谱法；LC-MS）显示，包括血管紧张素（1-5）、血管紧张素（1-7）和醛固酮在内的多种 RAAS 代谢物显著增加（<0.05）。与正常饲料饮食相比，草酸盐饮食可导致 SS 大鼠肾脏炎症、纤维化和肾功能障碍以及 RAAS 激活和高血压。本研究介绍了一种新的饮食诱导模型，用于研究高血压和 CKD，与现有模型相比，该模型更具有临床转化性和可重复性。
