Podocyte damage is a critical step in the development of glomerulosclerosis in the uninephrectomised-desoxycorticosterone hypertensive rat
Podocyte damage is a critical step in the development of glomerulosclerosis in the uninephrectomised-desoxycorticosterone hypertensive rat
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DOI：
10.1007/bf00230355
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发表时间：
2004
期刊：
影响因子：
3.5
通讯作者：
M. Kretzler;I. Koeppen-Hagemann;W. Kriz
中科院分区：
文献类型：
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作者：
M. Kretzler;I. Koeppen-Hagemann;W. Kriz
慢性单肾切除-脱氧皮质酮-三甲基乙酸（UNX-DOCA）高血压的进行性肾病模型与系膜增殖相关，是一种主要的疾病机制。尚未对该模型中伴随硬化发展的肾小球结构的改变进行详细的结构分析。雄性慕尼黑-威斯塔大鼠接受 UNX，每周注射醛固酮激动剂 DOCA 和 1% 氯化钠作为饮用溶液，并与假手术对照 (CON) 进行比较。发病后 38 天，UNX 动物的蛋白尿为 183±180 mg/天，而 CON 组为 0.38±0.22 mg/天。通过全身灌注固定肾脏，并处理肾组织以进行光学和电子显微镜检查。浅层和深部总肾小球体积从 CON 中的 2.18±0.15（深部：2.57±0.24）106μm3 增加到 UNX 中的 3.98±0.81（深部：3.95±0.63）106μm3。除了整体簇绒肥大之外，结构分析还显示，簇绒结构受到系膜扩张和/或毛细血管膨胀的严重破坏，导致局部簇绒增大。覆盖扩展区域的足细胞似乎无法适应覆盖增加的簇表面。它们的细胞结构出现严重损伤，导致肾小球基底膜（GBM）区域剥脱。 “裸露”GBM 似乎代表了透明变性、血栓形成和粘连形成的病灶，进而发展为节段性硬化症。在慢性肾小球高血压的UNX-DOCA模型中，经常遇到局部系膜扩张，但没有发现系膜增殖和基质产生进展到硬化的证据。该模型中肾小球的关键损伤似乎可归因于足细胞衰竭，由此产生的 GBM 剥脱引发粘连形成、透明变性并最终导致肾小球硬化。
The progressive renal disease model of chronic uninephrectomy-desoxycorticosterone-trimethylacetate (UNX-DOCA) hypertension is associated with mesangial proliferation as a major disease mechanism. A detailed structural analysis of the alterations in glomerular structure which accompany the development of sclerosis in this model has not been made. Male Munich-Wistar rats underwent UNX, received weekly injections of the aldosterone agonist DOCA and 1% sodium chloride as drinking solution and were compared with sham operated controls (CON). Thirty eight days after onset, UNX animals had an albuminuria of 183±180 mg/day versus 0.38±0.22 mg/day in CON. Kidneys were fixed by total body perfusion and renal tissue processed for light and electron-microscopy. Superficial and deep total glomerular volume increased from 2.18±0.15 (deep: 2.57±0.24) 106μm3in CON to 3.98±0.81 (deep: 3.95±0.63) 106μm3in UNX. In addition to overall tuft hypertrophy, structural analysis revealed severe destruction of tuft architecture with mesangial expansion and/or capillary ballooning, leading to local tuft enlargements. Podocytes overlying the expanded areas appeared unable to adapt to cover the increased tuft surfaces. They developed severe lesions in cell architecture leading to denudation of glomerular basement membrane (GBM)-areas. “Naked” GBM appears to represent a nidus for hyalinosis, thrombosis and synechia formation, which progresses to segmental sclerosis. In the UNX-DOCA model of chronic glomerular hypertension local mesangial expansion was frequently encountered but no evidence was found that mesangial proliferation and matrix production proceeded to sclerosis. The crucial damage to the glomerulus in this model would appear to be attributable to podocyte failure, with the resultant GBM denudation triggering synechia formation, hyalinosis and ultimately glomerulosclerosis.