Iacobini Carla, Menini Stefano, Ricci Carlo, Scipioni Angela, Sansoni Viola, Mazzitelli Giulia, Cordone Samantha, Pesce Carlo, Pugliese Francesco, Pricci Flavia, Pugliese Giuseppe
Department of Clinical Sciences, 'La Sapienza' University, Rome, Italy.
J Pathol. 2009 Jul;218(3):360-9. doi: 10.1002/path.2536.
Atherosclerosis and renal disease are related conditions, sharing several risk factors. This includes hyperlipidaemia, which may result in enhanced lipoprotein accumulation and chemical modification, particularly oxidation, with formation of advanced lipoxidation endproducts (ALEs). We investigated whether increased lipid peroxidation plays a major role in the pathogenesis of lipid-induced renal disease, via receptor-mediated mechanisms involving the scavenger and advanced glycation endproduct (AGE) receptors. Mice knocked out for galectin-3 (Gal3(-/-)), an AGE receptor previously shown to protect from AGE-induced renal injury, and the corresponding wild-type (Gal3(+/+)) animals, were fed an atherogenic high-fat diet (HFD; 15% fat, 1.25% cholesterol and 0.5% sodium cholate); mice fed a normal-fat diet (NFD; 4% fat) served as controls. Gal3(+/+) mice fed a HFD developed glomerular disease, as indicated by proteinuria, mesangial expansion and glomerular hypertrophy and sclerosis. Glomerular injury was associated with increased glomerular matrix protein expression, ALE and oxidized LDL content, oxidative stress, AGE and scavenger receptor expression and macrophage infiltration, with only modest renal/glomerular fat accumulation and changes in lipid metabolism. Fibrotic and inflammatory changes, together with accumulation of ALEs, such as 4-hydroxy-2-nonenal adducts and N(epsilon)-carboxymethyllysine, oxidative stress and expression of the receptor of AGEs (RAGE), were significantly more marked in Gal3(-/-) animals, whereas fat deposition and abnormalities in lipid metabolism remained modest. Thus, lipid-induced renal damage is mainly dependent on lipid peroxidation with formation of carbonyl reactive species and ALEs, which accumulate within the kidney tissue, thus triggering receptor-mediated pro-inflammatory signalling pathways, as in atherogenesis. Moreover, galectin-3 exerts a significant role in the uptake and effective removal of modified lipoproteins, with diversion of these products from RAGE-dependent pro-inflammatory pathways associated with downregulation of RAGE expression.
动脉粥样硬化和肾脏疾病是相关病症，具有若干共同的风险因素。这包括高脂血症，其可能导致脂蛋白积累增加和化学修饰，特别是氧化，形成晚期糖基化终产物（ALE）。我们研究了脂质过氧化增加是否通过涉及清道夫受体和晚期糖基化终产物（AGE）受体的受体介导机制在脂质诱导的肾脏疾病发病机制中起主要作用。敲除半乳糖凝集素-3（Gal3(-/-)）的小鼠（半乳糖凝集素-3是一种先前已证明可预防AGE诱导的肾损伤的AGE受体）和相应的野生型（Gal3(+/+)）动物，被喂食致动脉粥样硬化的高脂饮食（HFD；15%脂肪、1.25%胆固醇和0.5%胆酸钠）；喂食正常脂肪饮食（NFD；4%脂肪）的小鼠作为对照。喂食HFD的Gal3(+/+)小鼠出现了肾小球疾病，表现为蛋白尿、系膜扩张、肾小球肥大和硬化。肾小球损伤与肾小球基质蛋白表达增加、ALE和氧化型低密度脂蛋白含量增加、氧化应激、AGE和清道夫受体表达以及巨噬细胞浸润有关，仅有适度的肾脏/肾小球脂肪积累和脂质代谢变化。在Gal3(-/-)动物中，纤维化和炎症变化以及ALE（如4-羟基-2-壬烯醛加合物和N(ε)-羧甲基赖氨酸）的积累、氧化应激和AGE受体（RAGE）的表达明显更显著，而脂肪沉积和脂质代谢异常仍然适度。因此，脂质诱导的肾损伤主要依赖于脂质过氧化以及羰基反应性物种和ALE的形成，这些物质在肾脏组织内积累，从而触发受体介导的促炎信号通路，就像在动脉粥样硬化中一样。此外，半乳糖凝集素-3在摄取和有效清除修饰脂蛋白方面发挥重要作用，使这些产物从与RAGE表达下调相关的RAGE依赖性促炎途径中转移。
