Aberrant production of extracellular matrix proteins and dysfunction in kidney endothelial cells with a short duration of diabetes

作者：Grutzmacher Cathy; Park SunYoung; Zhao Yun; Morrison Margaret E; Sheibani Nader; Sorenson Christine M^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2013, 304(1): F19-F30.

DOI：10.1152/ajprenal.00036.2012

• angiogenesis
• capillary morphogenesis
• extracellular matrix proteins

Grutzmacher C, Park S, Zhao Y, Morrison ME, Sheibani N, Sorenson CM. Aberrant production of extracellular matrix proteins and dysfunction in kidney endothelial cells with a short duration of diabetes. Am J Physiol Renal Physiol 304: F19-F30, 2013. First published October 17, 2012; doi:10.1152/ajprenal.00036.2012.-Diabetic nephropathy is the most common cause of end-stage renal disease and is a major risk factor for cardiovascular disease. In the United States, microvascular complications during diabetic nephropathy contribute to high morbidity and mortality rates. However, the cell-autonomous impact of diabetes on kidney endothelial cell function requires further investigation. Male Akita/+ [autosomal dominant mutation in the insulin II gene (Ins2)] mice reproducibly develop diabetes by 4 wk of age. Here, we examined the impact a short duration of diabetes had on kidney endothelial cell function. Kidney endothelial cells were prepared from nondiabetic and diabetic mice (4 wk of diabetes) to delineate the early changes in endothelial cell function. Kidney endothelial cells from Akita/+ mice following 4 wk of diabetes demonstrated aberrant expression of extracellular matrix proteins including decreased osteopontin and increased fibronectin expression which correlated with increased alpha 5-integrin expression. These changes were associated with the attenuation of migration and capillary morphogenesis. Kidney endothelial cells from Akita/+ mice had decreased VEGF levels but increased levels of endothelial nitric oxide synthase(eNOS) and NO, suggesting uncoupling of VEGF-mediated NO production. Knocking down eNOS expression in Akita/+ kidney endothelial cells increased VEGF expression, endothelial cell migration, and capillary morphogenesis. Furthermore, attenuation of sprouting angiogenesis of aortas from Akita/+ mice with 8 wk of diabetes was restored in the presence of the antioxidant N-acetylcysteine. These studies demonstrate that aberrant endothelial cell function with a short duration of diabetes may set the stage for vascular dysfunction and rarefaction at later stages of diabetes.

• 出版日期2013-1