Yadranji Aghdam Saeed, Mahmoudpour Ali
Reynolds Institute on Aging, Room No. 4151, 629 Jack Stephens Drive, Little Rock, AR 72205, USA; Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Norgen Biotek Corp., 3430 Schmon Parkway, Thorold, ON, Canada L2V 4Y6.
Int J Nephrol. 2016;2016:3846573. doi: 10.1155/2016/3846573. Epub 2016 Oct 18.
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are major complications of type 1 and type 2 diabetes. DN and DR are mainly caused by injury to the perivascular supporting cells, the mesangial cells within the glomerulus, and the pericytes in the retina. The genes and molecular mechanisms predisposing retinal and glomerular pericytes to diabetic injury are poorly characterized. In this study, the genetic deletion of proteasome activator genes, PA28 and PA28 genes, protected the diabetic mice in the experimental STZ-induced diabetes model against renal injury and retinal microvascular injury and prolonged their survival compared with wild type STZ diabetic mice. The improved wellbeing and reduced renal damage was associated with diminished expression of Osteopontin (OPN) and Monocyte Chemoattractant Protein-1 (MCP-1) in the glomeruli of STZ-injected PA28/PA28 double knockout (Pa28DKO) mice and also in cultured mesangial cells and retinal pericytes isolated from Pa28DKO mice that were grown in high glucose. The mesangial PA28-mediated expression of OPN under high glucose conditions was suppressed by peptides capable of inhibiting the binding of PA28 to the 20S proteasome. Collectively, our findings demonstrate that diabetic hyperglycemia promotes PA28-mediated alteration of proteasome activity in vulnerable perivascular cells resulting in microvascular injury and development of DN and DR.
糖尿病肾病（DN）和糖尿病视网膜病变（DR）是1型和2型糖尿病的主要并发症。DN和DR主要是由血管周围支持细胞、肾小球内的系膜细胞以及视网膜中的周细胞损伤引起的。导致视网膜和肾小球周细胞易受糖尿病损伤的基因和分子机制目前尚不清楚。在本研究中，蛋白酶体激活基因PA28α和PA28β的基因缺失，在实验性链脲佐菌素诱导的糖尿病模型中保护糖尿病小鼠免受肾损伤和视网膜微血管损伤，并与野生型链脲佐菌素糖尿病小鼠相比延长了它们的生存期。与注射链脲佐菌素的PA28α/PA28β双敲除（Pa28DKO）小鼠肾小球中骨桥蛋白（OPN）和单核细胞趋化蛋白-1（MCP-1）表达降低相关，并且在从高糖培养的Pa28DKO小鼠分离的培养系膜细胞和视网膜周细胞中也降低。在高糖条件下，能够抑制PA28与20S蛋白酶体结合的肽抑制了系膜细胞中PA28介导的OPN表达。总的来说，我们的研究结果表明，糖尿病高血糖促进PA28介导的易损血管周围细胞中蛋白酶体活性改变，导致微血管损伤以及DN和DR的发展。
