论文部分内容阅读
Glomerular endothelial cell (GEC) injury plays an important role in the early stage of diabetic nephropathy (DN).Previous studies show that a PKCβ inhibitor is effective for treating DN.In the current study we further explored the effects and molecular mechanisms of PKCβ inhibitors on GEC apoptosis in DN in streptozotocin-induced diabetic mice in vivo and high glucose-or PMA-treated human renal glomerular endothelial cells (HRGECs) in vitro.In the diabetic mice,hyperglycemia caused aggravated nephropathy and GEC apoptosis accompanied by significantly increased expression of swiprosin-1,a potentally pro-apoptotic protein.Administration of LY333531 (1 mg·kg-1·d-1 for 8 weeks) significantly attenuated both GEC apoptosis and swiprosin-1 upregulation in the diabetic mice.Similar results were observed in high glucose-or PMA-treated HRGECs in vitro.The pro-apoptotic role of swiprosin-1 was further examined using HRGECs treated with lentivirus mediating RNA interference or over-expression and swiprosin-1-knockout mice.Over-expression of swiprosin-1 in HRGECs resulted in increases in apoptosis and in caspase-9,caspase-3 and Bax expression.In contrast,knockdown of swiprosin-1 attenuated high glucose-or PMA-induced HRGECs apoptosis.Furthermore,over-expression of swiprosin-1 promoted interaction between swiprosin-1 and caspase-9 and increased the formation of apoptosomes.In diabetic swiprosin-1-/-mice,the kidney/body weight,urinary albumin,glomerular hypertrophy,mitochondrial apoptotic-associated proteins and GEC apoptosis were significantly attenuated as compared with those in diabetic swiprosin-1+/+ mice.These results demonstrate that swiprosin-1 is up-regulated by PKCβ in the early stage of DN,and that PKCβ facilitates GEC apoptosis through the mitochondrial-dependent pathway.