Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?
Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?
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DOI：
10.1152/ajprenal.00313.2016
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Marshall CB
中科院分区：
文献类型：
--
作者：
Marshall CB
糖尿病肾病（DN）是美国慢性肾病的主要原因，也是心血管疾病和死亡的主要原因。DN在临床表现（包括微量白蛋白尿和肾小球滤过率（GFR）下降）明显之前的数年内不知不觉地发展。在临床无症状期，出现结构性病变，包括肾小球基底膜（GBM）增厚、系膜扩张和肾小球硬化。一旦微量白蛋白尿临床表现明显，结构性病变往往是相当先进的，GFR下降，然后可能会迅速进行到终末期肾病。鉴于目前缺乏用于检测早期DN的敏感生物标志物，重点转向检查DN中最早结构变化的细胞和分子基础，即，GBM增厚，可能是必要的。在糖尿病发病后的一到两年内观察到，GBM增厚先于临床上明显的蛋白尿。在成熟的肾小球中，足细胞在生理和病理状态下都可能是修饰GBM、合成和组装基质组分的关键。足细胞还分泌基质金属蛋白酶，细胞外基质周转的关键介质。研究表明，关键的足细胞-GBM界面在糖尿病环境中被破坏。就像健康的足细胞对于维持正常的GBM结构和功能是必不可少的一样，受损的足细胞可能在破坏GBM的合成和降解途径之间的平衡中起着重要作用。本文将通过回顾GBM的形成、健康期间的维持和DN中的破坏来探讨GBM增厚在DN中的生物学意义。
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease in the United States and is a major cause of cardiovascular disease and death. DN develops insidiously over a span of years before clinical manifestations, including microalbuminuria and declining glomerular filtration rate (GFR), are evident. During the clinically silent period, structural lesions develop, including glomerular basement membrane (GBM) thickening, mesangial expansion, and glomerulosclerosis. Once microalbuminuria is clinically apparent, structural lesions are often considerably advanced, and GFR decline may then proceed rapidly toward end-stage kidney disease. Given the current lack of sensitive biomarkers for detecting early DN, a shift in focus toward examining the cellular and molecular basis for the earliest structural change in DN, i.e., GBM thickening, may be warranted. Observed within one to two years following the onset of diabetes, GBM thickening precedes clinically evident albuminuria. In the mature glomerulus, the podocyte is likely key in modifying the GBM, synthesizing and assembling matrix components, both in physiological and pathological states. Podocytes also secrete matrix metalloproteinases, crucial mediators in extracellular matrix turnover. Studies have shown that the critical podocyte-GBM interface is disrupted in the diabetic milieu. Just as healthy podocytes are essential for maintaining the normal GBM structure and function, injured podocytes likely have a fundamental role in upsetting the balance between the GBM’s synthetic and degradative pathways. This article will explore the biological significance of GBM thickening in DN by reviewing what is known about the GBM’s formation, its maintenance during health, and its disruption in DN.
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