Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy.
Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy.
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DOI：
10.1530/joe-13-0167
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
Conover CA
中科院分区：
文献类型：
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作者：
Mader JR;Resch ZT;McLean GR;Mikkelsen JH;Oxvig C;Marler RJ;Conover CA
我们研究了妊娠相关血浆蛋白-A(PAPP-A)在糖尿病肾病中的作用。正常人肾脏中PAPP-A在肾小球中呈特异性染色，糖尿病组肾小球中PAPP-A的染色明显增强。为了评估PAPP-A在糖尿病肾病发展中的可能作用，我们用链脲佐菌素诱导14月龄野生型(WT)和PAPP-A基因敲除(KO)小鼠糖尿病。在稳定的高血糖4个月后进行肾脏组织病理学评估。WT糖尿病小鼠的肾脏表现出多种异常，包括鲍曼囊增厚(100%)、肾小球增大(80%)、肾小管扩张(80%)和单个核细胞浸润(90%)。年龄匹配的非糖尿病WT鼠的肾脏有类似于糖尿病WT鼠的肾小管扩张和单个核细胞浸润的证据，表明这些变化主要与年龄有关。然而，鲍曼囊增厚和肾小球增大似乎是实验性糖尿病所特有的。糖尿病PAPP-A KO小鼠的肾脏显著减少，或没有证据表明Bowman‘s包膜增厚和肾小球大小发生变化。与PAPP-A KO小鼠相比，糖尿病WT组也有更大的系膜面积和更多的巨噬细胞染色。综上所述，肾小球中PAPP-A的高表达与人类糖尿病肾病有关，而PAPP-A的缺失与小鼠糖尿病肾病指标的发展抵抗有关。这些数据表明PAPP-A是糖尿病肾病的潜在治疗靶点。
We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old wild-type (WT) and PAPP-A knock-out (KO) mice. Renal histopathology was evaluated after four months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman’s capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration as diabetic WT mice indicating that these changes were predominantly age-related. However, thickened Bowman’s capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic PAPP-A KO mice had significantly reduced or no evidence of changes in Bowman’s capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT compared to PAPP-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.