Reversibility of glucose-induced changes in mesangial cell extracellular matrix depends on the genetic background
Reversibility of glucose-induced changes in mesangial cell extracellular matrix depends on the genetic background
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DOI：
10.2337/diabetes.51.2.499
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发表时间：
2002-02-01
期刊：
影响因子：
7.7
通讯作者：
Striker, GE
中科院分区：
文献类型：
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作者：
Fornoni, A;Striker, LJ;Striker, GE
充分的血糖控制可保护大多数糖尿病患者免于肾病，但尽管降低了血糖，仍有相当一部分患者发生疾病进展。我们从小鼠品系的肾小球中分离出肾小球系膜细胞（MC），所述小鼠品系在糖尿病患者中模拟这两种结果，即具有发展进行性糖尿病肾病的倾向（ROP）或抗性（B6）的那些。我们确定了在慢性暴露于升高的葡萄糖浓度后，选定的细胞外基质相关分子变化的性质和可逆性。MC暴露于25 mmol/l葡萄糖5周，随后暴露于6 mmol/l葡萄糖和19 mmol/l甘露醇5周。暴露于25 mmol/l葡萄糖的B6 MC中基质金属蛋白酶-2（MMP-2）和转化生长因子-β（1）（TGF-β（1））水平升高，但当葡萄糖浓度降至6 mmol/l时恢复至基线水平。MMP-2和TGF-β（1）在ROP MC中基线时较高，并在25 mmol/l葡萄糖时升高，但在葡萄糖浓度降低时仍升高。在B6 MC暴露于25 mmol/l葡萄糖时，I型胶原表达和积累以可逆的方式增加。然而，I型胶原蛋白表达在ROP MC中在基线时较高，并且不受葡萄糖浓度变化的影响。因此，25 mmol/l葡萄糖诱导抗硬化小鼠MC中MMP-2、TGF-β（1）和I型胶原蛋白的可逆变化，但在易硬化小鼠MC中不诱导这种变化。因此，进行性糖尿病肾病可能继发于MC表型的稳定改变，这是遗传背景和葡萄糖浓度升高之间相互作用的结果。
Adequate glycemic control protects most patients with diabetes from nephropathy, but a substantial fraction of patients develop progressive disease despite lowering glycemia. We isolated mesangial cells (MC) from the glomeruli of mouse strains that model these two outcomes in patients with diabetes, namely those that have the propensity (ROP) or resistance (B6) to develop progressive diabetic nephropathy. We determined the nature and reversibility of changes in selected extracellular matrix-related molecules after chronic exposure to elevated glucose concentration. MC were exposed to 25 mmol/l glucose for 5 weeks followed by 6 mmol/l glucose and 19 mmol/l mannitol for an additional 5 weeks. Matrix metalloproteinase-2 (MMP-2) and transforming growth factor-beta(1) (TGF-beta(1)) levels increased in B6 MC exposed to 25 mmol/l glucose but returned to baseline levels when the glucose concentration was reduced to 6 mmol/l. MMP-2 and TGF-beta(1) were higher in ROP MC at baseline and increased in response to 25 mmol/l glucose, but remained elevated when glucose concentration was reduced. Type I collagen expression and accumulation increased in a reversible manner in B6 MC exposed to 25 mmol/1 glucose. However, type I collagen expression was higher in ROP MC at baseline and remained unaffected by changes in glucose concentration. Thus, 25 mmol/l glucose induced reversible changes in MMP-2, TGF-beta(1), and type I collagen in MC of sclerosis-resistant mice but not in MC from sclerosis-prone mice. Therefore, progressive diabetic nephropathy may be secondary to stable alterations in the phenotype of MC as a result of the interplay between the genetic background and elevated glucose concentrations.