Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease
Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease
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DOI：
10.1681/asn.v1191656
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发表时间：
2000-09-01
影响因子：
13.6
通讯作者：
D'Agati, VD
中科院分区：
文献类型：
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作者：
Tanji, N;Markowitz, GS;D'Agati, VD
晚期糖基化终产物(AGE)通过两种主要机制参与糖尿病组织损伤，即通过非酶糖化改变细胞外基质结构，形成蛋白质交联链，以及通过与特定的细胞表面受体相互作用调节细胞功能，其中最具特点的是AGE受体(RAGE)。最近的证据表明，炎症过程和细胞氧化损伤也可能促进AGE-RAGE的相互作用。为了研究AGE和RAGE在糖尿病肾脏中的分布特点，并确定其对糖尿病肾病的特异性，对糖尿病肾病(n=26)、高血压肾硬化(n=7)、特发性局灶节段性肾小球硬化(n=II)、肥胖局灶性硬化(n=7)、狼疮性肾炎(n=11)和正常对照组(n=2)的肾活检标本进行了免疫组织化学分析。弥漫性和结节性糖尿病肾病的AGE检测结果相同。慢性粒细胞白血病主要见于糖尿病肾小球系膜(96%)、肾小球基底膜(42%)、肾小管基底膜(85%)和血管壁(96%)。在糖尿病肾病中，Pent主要分布于间质胶原(90%)，较少见于血管壁(54%)、系膜(77%)、肾小球基底膜(4%)和肾小管基底膜(31%)。RAGE在正常足细胞上表达，在糖尿病肾病中表达上调。通过对显微解剖的肾组织进行逆转录-聚合酶链式反应(RT-PCR)分析，证实RAGE基因在肾小球中的表达受到限制。根据病理评估，CML的系膜和GEM免疫反应的程度与糖尿病肾小球硬化的严重程度相关，而不是Pent。在特发性和继发性局灶性节段性肾小球硬化、高血压肾硬化症和狼疮性肾炎的肾小球硬化和动脉硬化区也发现了CML和Pent。在活动期狼疮性肾炎中，CML和Pent在增生性肾小球小球和新月体中均可检测到。综上所述，慢性粒细胞白血病是糖尿病肾病肾脏基底膜的主要增龄期，其积聚涉及足细胞RAGE的上调。AGE在继发于系统性红斑狼疮的急性炎症性肾小球肾炎中也会积聚，可能是通过对肾小球基质蛋白的酶催化氧化。
Advanced glycation end products (AGE) contribute to diabetic tissue injury by two major mechanisms, i.e., the alteration of extracellular matrix architecture through nonenzymatic glycation, with formation of protein crosslinks, and the modulation of cellular functions through interactions with specific cell surface receptors, the best characterized of which is the receptor for AGE (RAGE). Recent evidence suggests that the AGE-RAGE interaction may also be promoted by inflammatory processes and oxidative cellular injury. To characterize the distributions of AGE and RAGE in diabetic kidneys and to determine their specificity for diabetic nephropathy, an immunohistochemical analysis of renal biopsies from patients with diabetic nephropathy (n = 26), hypertensive nephrosclerosis (n = 7), idiopathic focal segmental glomerulosclerosis (n = ii), focal sclerosis secondary to obesity (n = 7), and lupus nephritis (n = 11) and from normal control subjects (n = 2) was performed, using affinity-purified antibodies raised to RAGE and two subclasses of AGE, i.e., N-epsilon-(carboxymethyl)lysine (CML) and pentosidine (PENT). AGE were detected equally in diffuse and nodular diabetic nephropathy. CML was the major AGE detected in diabetic mesangium (96%), glomerular basement membranes (GBM) (42%), tubular basement membranes (85%), and vessel walls (96%). In diabetic nephropathy, PENT was preferentially located in interstitial collagen (90%) and was less consistently observed in vessel walls (54%), mesangium (77%), GEM (4%), and tubular basement membranes (31%). RAGE was expressed on normal podocytes and was upregulated in diabetic nephropathy. The restriction of RAGE mRNA expression to glomeruli was confirmed by reverse transcription-PCR analysis of microdissected renal tissue compartments. The extent of mesangial and GEM immunoreactivity for CML, but not PENT, was correlated with the severity of diabetic glomerulosclerosis, as assessed pathologically. CML and PENT were also identified in areas of glomerulosclerosis and arteriosclerosis in idiopathic and secondary focal segmental glomerulosclerosis, hypertensive nephrosclerosis, and lupus nephritis. In active lupus nephritis, CML and PENT were detected in the proliferative glomerular tufts and crescents. In conclusion, CML is a major AGE in renal basement membranes in diabetic nephropathy, and its accumulation involves upregulation of RAGE on podocytes. AGE are also accumulated in acute inflammatory glomerulonephritis secondary to systemic lupus erythematosus, possibly via enzymatic oxidation of glomerular matrix proteins.