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Kidney Week

Abstract: TH-PO713

NO and SIRT1 Protect Glomerular Endothelial Cells with TERC Deletion from Hyperglycemia-Induced Senescence

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental


  • Cheng, Huifang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Endothelial dysfunction plays an important role in the development of diabetic nephropathy (DN). We have previously reported that telomerase deficiency may predispose to diabetic renal injury.


To investigate the role of nitric oxide (NO) and SIRT1 in mediation of telomerase-dependent vulnerability to DN, we used streptozotocin (STZ) to induce diabetes in fourth generation (G4) TerC /T KO mice and compared their response with wild type (Wt) in response to treatment with NO precursor, L-arginine (L-arg). We also used primary cultured glomerular endothelial cells (GEnCs) for in vitro studies to explore the interaction of NO and SIRT1.


STZ induced similar hyperglycemia, but TERC/T KO mice had increased renal involvement, which was alleviated by L-arg administration, with decreased albuminuria and less GBM thickening. Increased cell senescence and more severe oxidative stress was seen in diabetic mice with TERC/T deficiency, indicated by higher urinary F2-isoprostane and accumulation of renal nitrotyrosine. L-arg treatment partially ameliorated those alterations. In addition, L-arg limited the reduction in SIRT1 expression, associated with decreased senescence in the diabetic kidney, especially with telomerase deficiency. Ex vivo study with freshly isolated de-capsulated glomeruli demonstrated that high glucose (HG, 30 mM) incubation stimulated endothelial cell detachment from GBM in glomeruli with TERC deletion, which could be prevented by co-incubation with a SIRT activator, SRT1720.
Primary cultured GEnCs exhibited reduced NO and cellular senescence after incubation for 96 hours in HG medium, with a marked increase in cells with TERC deletion. HG also decreased SIRT 1 expression and activity to a greater extent in the TERC deficient GEnCs. SRT1720 partially restored NO expression, and co-incubation with either SRT1720 or L-arg attenuated HG induced senescence in TERC deleted GEnCs.


These results suggested that both NO and the SIRT1 pathway are involved in the telomerase dependent susceptibility to DN progression and GEnCs senescence.


  • NIDDK Support