Perazza Laís R, Mitchell Patricia L, Lizotte Farah, Jensen Benjamin A H, St-Pierre Philippe, Trottier Jocelyn, Barbier Olivier, Mathieu Patrick, Geraldes Pedro M, Marette André
Quebec Heart and Lung Institute, Laval University, Quebec, QC, Canada.
Institute of Nutrition and Functional Foods, Laval University, Quebec, QC, Canada.
FASEB J. 2021 May;35(5):e21559. doi: 10.1096/fj.202100073R.
Diabetic nephropathy (DN) remains the major cause of end-stage renal disease (ESRD). We used high-fat/high-sucrose (HFHS)-fed LDLr /ApoB mice with transgenic overexpression of IGFII in pancreatic β-cells (LRKOB100/IGFII) as a model of ESRD to test whether dietary long chain omega-3 polyunsaturated fatty acids LCω3FA-rich fish oil (FO) could prevent ESRD development. We further evaluated the potential of docosahexaenoic acid (DHA)-derived pro-resolving lipid mediators, 17-hydroxy-DHA (17-HDHA) and Protectin DX (PDX), to reverse established ESRD damage. HFHS-fed vehicle-treated LRKOB100/IGFII mice developed severe kidney dysfunction leading to ESRD, as revealed by advanced glomerular fibrosis and mesangial expansion along with reduced percent survival. The kidney failure outcome was associated with cardiac dysfunction, revealed by reduced heart rate and prolonged diastolic and systolic time. Dietary FO prevented kidney damage, lean mass loss, cardiac dysfunction, and death. 17-HDHA reduced podocyte foot process effacement while PDX treatment alleviated kidney fibrosis and mesangial expansion as compared to vehicle treatment. Only PDX therapy was effective at preserving the heart function and survival rate. These results show that dietary LCω3FA intake can prevent ESRD and cardiac dysfunction in LRKOB100/IGFII diabetic mice. Our data further reveals that PDX can protect against renal failure and cardiac dysfunction, offering a potential new therapeutic strategy against ESRD.
糖尿病肾病（DN）仍然是终末期肾病（ESRD）的主要病因。我们使用高脂/高糖（HFHS）喂养的LDLr /ApoB小鼠，其胰腺β细胞中IGFII转基因过表达（LRKOB100/IGFII）作为ESRD模型，以测试富含长链ω-3多不饱和脂肪酸（LCω3FA）的鱼油（FO）能否预防ESRD的发展。我们进一步评估了二十二碳六烯酸（DHA）衍生的促消退脂质介质17-羟基-DHA（17-HDHA）和保护素DX（PDX）逆转已建立的ESRD损伤的潜力。HFHS喂养的溶剂处理的LRKOB100/IGFII小鼠出现严重的肾功能障碍，导致ESRD，表现为晚期肾小球纤维化和系膜扩张以及存活率降低。肾衰竭结果与心脏功能障碍相关，表现为心率降低以及舒张期和收缩期时间延长。饮食中的FO可预防肾脏损伤、瘦体重减轻、心脏功能障碍和死亡。与溶剂处理相比，17-HDHA减少了足细胞足突消失，而PDX治疗减轻了肾脏纤维化和系膜扩张。只有PDX疗法在维持心脏功能和存活率方面有效。这些结果表明，饮食中摄入LCω3FA可以预防LRKOB100/IGFII糖尿病小鼠的ESRD和心脏功能障碍。我们的数据进一步表明，PDX可以预防肾衰竭和心脏功能障碍，为对抗ESRD提供了一种潜在的新治疗策略。
