Glomerular cell death and inflammation with high-protein diet and diabetes
Glomerular cell death and inflammation with high-protein diet and diabetes
复制标题
DOI：
10.1093/ndt/gfs579
复制
发表时间：
2013-07-01
影响因子：
6.1
通讯作者：
Tuttle, Katherine R.
中科院分区：
文献类型：
--
作者：
Meek, Rick L.;LeBoeuf, Renee C.;Tuttle, Katherine R.
背景过量摄入氨基酸（AAs）会增加细胞对晚期糖基化终产物（AGEs）的暴露，这是蛋白质摄入加重糖尿病肾病（DKD）的一种机制。本研究通过体内概念验证评估，评估了体外暴露于高蛋白饮食和/或糖尿病代谢应激特征的肾小球细胞中AGE（AGE）介导的凋亡和炎症的受体。在对照和代谢应激条件下培养小鼠足细胞和系膜细胞：（i）不添加;（ii）增加的AA（4-6倍于对照）;（iii）高葡萄糖（HG，30.5mM）;（iv）AA/HG组合;（v）AGE-牛血清白蛋白（AGE-BSA，300 μ g/mL）;（vi）BSA（300 μ g/mL）。阻断抗体可抑制细胞凋亡。糖尿病小鼠（链脲佐菌素）和非糖尿病小鼠（C57 BL/6 J）食用蛋白质热量为20%或40%（高）的饮食20周。DKD患者和对照组均提供24小时尿标本。在足细胞和系膜细胞，凋亡（半胱天冬酶3/7活性和TUNEL）在所有代谢应激条件下增加。炎症介质表达（实时逆转录聚合酶链反应：血清淀粉样蛋白A、半胱天冬酶-4、诱导型一氧化氮合酶和单核细胞趋化蛋白-1）和免疫组化（免疫染色）也增加。抑制足细胞凋亡和炎症。在喂食高蛋白质的小鼠中，糖尿病组的足细胞数量（WT-1免疫染色）减少，只有这些糖尿病小鼠出现蛋白尿。DKD患者和对照组蛋白质摄入量（尿素氮）与AGE排泄量（羧甲基赖氨酸）相关。高蛋白饮食和/或糖尿病样条件增加肾小球细胞死亡和炎症，反应介导的RAGE在足细胞。高蛋白饮食加剧DKD早期指标的概念得到了来自小鼠和人的数据的支持。
Background. Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo.Methods. Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4-6-fold >control); (iii) high glucose (HG, 30.5 mM); (iv) AA/HG combination; (v) AGE-bovine serum albumin (AGE-BSA, 300 mu g/mL); (vi) BSA (300 mu g/mL). RAGE was inhibited by blocking antibody. Diabetic (streptozotocin) and nondiabetic mice (C57BL/6J) consumed diets with protein calories of 20 or 40% (high) for 20 weeks. People with DKD and controls provided 24-h urine samples.Results. In podocytes and mesangial cells, apoptosis (caspase 3/7 activity and TUNEL) increased in all metabolic stressor conditions. Both inflammatory mediator expression (real-time reverse transcriptase-polymerase chain reaction: serum amyloid A, caspase-4, inducible nitric oxide synthase, and monocyte chemotactic protein-1) and RAGE (immunostaining) also increased. RAGE inhibition prevented apoptosis and inflammation in podocytes. Among mice fed high protein, podocyte number (WT-1 immunostaining) decreased in the diabetic group, and only these diabetic mice developed albuminuria. Protein intake (urea nitrogen) correlated with AGE excretion (carboxymethyllysine) in people with DKD and controls.Conclusions. High-protein diet and/or diabetes-like conditions increased glomerular cell death and inflammation, responses mediated by RAGEs in podocytes. The concept that high-protein diets exacerbate early indicators of DKD is supported by data from mice and people.