The Endoplasmic Reticulum Stress Protein Calreticulin in Diabetic Chronic Kidney Disease
Abstract
We hypothesize that ER stress induced by glucose in diabetes promotes diabetic CKD through CRT stimulation of TGF-beta-dependent calcium/NFAT signaling in renal proximal tubule cells. In Aim 1 we will determine the role of CRT in mediating the fibrogenic effects of TGF-beta and glucose in renal cells. In Aim 2, we will determine the role of CRT in mouse models of diabetic nephropathy. In year 2, we developed stably transduced HK-2 cells using lentivirus to enable us to perform long term studies in culture. Importantly, we performed animal studies this year, which showed that ultrasound mediated delivery of cre-recombinase plasmid to CRT floxed mice reduces CRT expression by ~30-40 with primary down regulation in the tubules which persisted over 5 months. Down regulation of CRT expression in diabetic CRT floxed mice showed a significant reduction in the urinary albumin/creatinine ratio, indicating attenuation of renal dysfunction, and improved survival. We also saw reduced fibrosis by electron microscopy and PAS staining and by western blot for fibronectin.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2016
- Accession Number
- AD1017274
Entities
People
- Joanne E Murphy-Ullrich
Organizations
- University of Alabama at Birmingham