Renal tubular basement membrane and collagen type IV in diabetes mellitus.
Renal tubular basement membrane and collagen type IV in diabetes mellitus.
复制标题
DOI：
10.1038/ki.1993.19
复制
发表时间：
1993
影响因子：
19.6
通讯作者：
F. Ziyadeh
中科院分区：
文献类型：
--
作者：
F. Ziyadeh
糖尿病中的肾小管基底膜和 IV 型胶原。糖尿病肾病多结构性病变的发病机制仍存在争议，并且可能是多因素的。衬在肾小球和肾小管元件上的肾基底膜均匀增厚似乎是与高血糖直接相关的代谢扰动的结果。虽然大多数研究都集中在肾小球基底膜和系膜中细胞外基质积累的增加及其与肾小球功能紊乱的关系，但对于肾小管间质变化和增厚的肾小管基底膜（TBM）的发病机制和意义知之甚少。后面这些变化可能与 TBM 内的肾小管上皮细胞肥大有因果关系。据推测，在疾病的早期阶段，高血糖会诱导肾小管肥大并刺激各种基质成分的合成，这些基质成分是TBM的正常成分。随后，TBM 的结构组成容易受到非酶糖基化的进一步修饰，这种异常过程可能会对基质降解产生相对的抵抗力，从而导致周转缓慢。对培养的小鼠近曲小管细胞的体外研究提供的证据表明，升高的环境葡萄糖足以刺激细胞肥大和增加 IV 型胶原（TBM 的主要成分）的生物合成。高葡萄糖水平会增加稳态 IV 型胶原 mRNA，部分原因是该基因顺式作用元件的转录激活，这些元件由假定的葡萄糖响应反式作用蛋白控制。高血糖的这种影响可能是多元醇途径活性增加的结果，伴随着细胞肌醇代谢的改变。用索宾尼尔（一种醛糖还原酶抑制剂）进行治疗，或在培养基中补充超生理水平的肌醇，可防止高葡萄糖刺激 IV 型胶原蛋白的分泌和生物合成增加。然而，葡萄糖诱导的细胞肥大受这些操作的影响很小，并且可能是由于体液或局部介质（包括转化生长因子-β）的激活所致。
Renal tubular basement membrane and collagen type IV in diabetes mellitus. The pathogenesis of the multiple structural lesions in diabetic nephropathy remains debated, and likely is multifactorial. The uniform thickening of the renal basement membranes lining the glomerular and tubular elements appears to be a consequence of the metabolic perturbations which are directly related to hyperglycemia. While most investigations have focused on the increased accumulation of extracellular matrix in the glomerular basement membrane and the mesangium, and their relation to derangements in glomerular function, little is known regarding the pathogenesis and the significance Of the tubulointerstitial changes and the thickened tubular basement membrane (TBM). It is possible that these latter changes are causally related to the cellular hypertrophy of the renal tubular epithelium that lines the TBM. It has been postulated that in the earlier stages of the disease, hyperglycemia induces renal tubular hypertrophy and stimulates the synthesis of the various matrix components which are normal constituents of the TBM. Later, the structural composition of the TBM is susceptible to further modifications by non-enzymatic glycation, and this aberrant process may impart a relative resistance to matrix degradation leading to a slow turnover. In vitro investigations on murine proximal tubule cells in culture have provided evidence that elevated ambient glucose is a sufficient stimulus for cellular hypertrophy and increased biosynthesis of collagen type IV, the predominant constituent of TBM. High glucose levels increase steady-state collagen IV mRNA, partly due to transcriptional activation ofcis-acting elements of the gene which are controlled by putative glucose-responsivetrans-acting proteins. This effect of hyperglycemia may be the consequence of increased activity of the polyol pathway, with attendant alterations in cellularmyo-inositol metabolism. Treatment with sorbinil, an aldose reductase inhibitor, or supplementation of the medium with supra-physiologic levels ofmyo-inositol, prevents the stimulation by high glucose of the increased secretion and biosynthesis of collagen IV. The glucose-induced cellular hypertrophy, however, is minimally aifected by these maneuvers, and may result from activation of humoral or local mediators including transforming growth factor-β.