Coimbra T M, Janssen U, Gröne H J, Ostendorf T, Kunter U, Schmidt H, Brabant G, Floege J
Divisions of Nephrology, Medizinische Hochschule, Hannover, Germany.
Kidney Int. 2000 Jan;57(1):167-82. doi: 10.1046/j.1523-1755.2000.00836.x.
Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes.
More than half of the new patients admitted to dialysis therapy in some centers are diagnosed with type IIb diabetes, that is, diabetes associated with obesity. This study searched for a common final pathway of renal damage in this progressive renal disease.
The evolution of biochemical and morphological renal changes was examined in 6- to 60-week-old Zucker rats (fa/fa-rats), a model of obesity associated with type II diabetes.
fa/fa-rats exhibited pronounced hyperinsulinemia and hyperlipidemia at 6 weeks and became diabetic after 14 weeks of age. Significant focal segmental glomerulosclerosis was first noted in 18-week-old fa/fa-rats and tubulointerstitial damage and proteinuria in 40-week-old fa/fa-rats. A comparison of kidneys of six-week-old fa/fa-and lean control (Fa/?) rats by immunohistology revealed a 1.8-fold increase in glomerular monocyte/macrophage counts in fa/fa-rats and a significant increase in de novo desmin expression in podocytes. Electron microscopy demonstrated an increase in the number of podocyte mitochondria and intracytoplasmic protein and fat droplets. Podocyte desmin scores markedly increased until week 18 in fa/fa-rats, whereas glomerular monocyte/macrophage counts peaked at 3.2-fold at week 14. Podocyte desmin expression, but not glomerular macrophage infiltration, correlated with damage in adjacent tubular cells, as evidenced by their de novo expression of vimentin. Progressive glomerular hypertrophy was detected in fa/fa-rats after 10 weeks. GBM width was significantly increased in 14-week-old fa/fa-rats as compared with lean controls. Mesangial cell activation (de novo expression of alpha-smooth muscle actin) and proliferation was low to absent throughout the observation period in fa/fa-rats. Renal cell death counts (TUNEL) remained unchanged in 6- to 40-week-old fa/fa-rats. Tubulointerstitial myofibroblast formation and matrix accumulation occurred late during the study duration in fa/fa-rats.
These data suggest that early progressive podocyte damage and macrophage infiltration is associated with hyperlipidemia and type IIb diabetes mellitus, and antedates both the development of glomerulosclerosis and tubulointerstitial damage.
肥胖 Zucker（脂肪）大鼠患 II 型糖尿病时导致肾损伤的早期事件。
在一些中心，超过一半新接受透析治疗的患者被诊断为 IIb 型糖尿病，即与肥胖相关的糖尿病。本研究探寻了这种进行性肾脏疾病中肾损伤的共同最终途径。
在 6 至 60 周龄的 Zucker 大鼠（fa/fa 大鼠）中检查肾脏生化和形态学变化的演变，该大鼠是与 II 型糖尿病相关的肥胖模型。
fa/fa 大鼠在 6 周时表现出明显的高胰岛素血症和高脂血症，并在 14 周龄后患上糖尿病。在 18 周龄的 fa/fa 大鼠中首次发现明显的局灶节段性肾小球硬化，在 40 周龄的 fa/fa 大鼠中出现肾小管间质损伤和蛋白尿。通过免疫组织学比较 6 周龄 fa/fa 大鼠和瘦对照（Fa/?）大鼠的肾脏，发现 fa/fa 大鼠肾小球单核细胞/巨噬细胞计数增加了 1.8 倍，足细胞中结蛋白的从头表达显著增加。电子显微镜显示足细胞线粒体数量增加以及胞浆内蛋白质和脂肪滴增加。在 fa/fa 大鼠中，足细胞结蛋白评分在 18 周前显著增加，而肾小球单核细胞/巨噬细胞计数在第 14 周达到峰值，为 3.2 倍。足细胞结蛋白表达与相邻肾小管细胞损伤相关，而肾小球巨噬细胞浸润则无此关联，这可通过肾小管细胞中波形蛋白的从头表达得到证明。在 10 周后，fa/fa 大鼠中检测到进行性肾小球肥大。与瘦对照相比，14 周龄 fa/fa 大鼠的肾小球基底膜宽度显著增加。在整个观察期内，fa/fa 大鼠系膜细胞活化（α-平滑肌肌动蛋白的从头表达）和增殖程度较低或无。在 6 至 40 周龄的 fa/fa 大鼠中，肾细胞死亡计数（TUNEL）保持不变。在研究期间后期，fa/fa 大鼠出现肾小管间质肌成纤维细胞形成和基质积聚。
这些数据表明，早期进行性足细胞损伤和巨噬细胞浸润与高脂血症和 IIb 型糖尿病相关，且早于肾小球硬化和肾小管间质损伤的发生。
