Cohen Margo P, Ziyadeh Fuad N, Hong Soon Won, Shearman Clyde W, Hud Elizabeth, Lautenslager Gregory T, Iglesias-de la Cruz M Carmen, Chen Sheldon
Institute of Metabolic Research and Exocell, University City Science Center, Philadelphia, PA 19104, USA.
Kidney Int. 2002 Jun;61(6):2025-32. doi: 10.1046/j.1523-1755.2002.00352.x.
Glycated albumin has been causally linked to the pathobiology of diabetic renal disease through its ability to stimulate the expression of transforming growth factor-beta1 (TGF-beta1), activate protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), and promote production of extracellular matrix proteins in cultured glomerular cells. Whether glycated albumin modulates glomerular TGF-beta1 expression in vivo is not known. To address this issue, we assessed glomerular TGF-beta1 expression and pathology in response to reducing the burden of glycated albumin in vivo.
We measured serum glycated albumin, urine protein, glomerular TGF-beta1 expression and morphometry, and collagen IV and fibronectin mRNA in db/m and db/db controls and in db/db mice treated for eight weeks with a synthetic compound that inhibits the condensation of glucose with albumin.
In situ hybridization studies showed markedly increased glomerular TGF-beta1 mRNA in control db/db mice, which was significantly reduced in db/db mice treated for eight weeks with test compound. The treatment protocol, which normalized serum glycated albumin, concomitantly reduced the elevated protein excretion and the renal overexpression of mRNAs encoding fibronectin and collagen IV, and significantly decreased the mesangial matrix expansion, observed in db/db control animals.
These findings, to our knowledge, provide the first evidence that glomerular overexpression of TGF-beta1 in diabetes derives at least in part from elevated glycated albumin concentrations, and can be partially suppressed by inhibiting the formation of this glycated protein. The results further suggest that glycated albumin has an important nephropathogenic role in diabetes that is operative, and can be therapeutically addressed, independent of glycemic status.
糖化白蛋白通过刺激转化生长因子-β1（TGF-β1）的表达、激活蛋白激酶C（PKC）和细胞外信号调节激酶（ERK）以及促进培养的肾小球细胞中细胞外基质蛋白的产生，与糖尿病肾病的病理生物学存在因果关系。糖化白蛋白是否在体内调节肾小球TGF-β1的表达尚不清楚。为了解决这个问题，我们评估了体内糖化白蛋白负担减轻后肾小球TGF-β1的表达和病理情况。
我们测量了db/m和db/db对照组以及用抑制葡萄糖与白蛋白缩合的合成化合物治疗8周的db/db小鼠的血清糖化白蛋白、尿蛋白、肾小球TGF-β1的表达和形态学，以及IV型胶原和纤连蛋白mRNA。
原位杂交研究显示，对照db/db小鼠肾小球TGF-β1 mRNA显著增加，在用测试化合物治疗8周的db/db小鼠中显著降低。该治疗方案使血清糖化白蛋白正常化，同时减少了db/db对照动物中观察到的升高的蛋白排泄以及编码纤连蛋白和IV型胶原的mRNA的肾脏过表达，并显著减少了系膜基质扩张。
据我们所知，这些发现首次证明糖尿病中肾小球TGF-β1的过表达至少部分源于糖化白蛋白浓度升高，并且通过抑制这种糖化蛋白的形成可以部分抑制。结果进一步表明，糖化白蛋白在糖尿病中具有重要的致肾病作用，这种作用是独立于血糖状态起作用的，并且可以通过治疗解决。
