Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling

• Published in: Cellular signalling Vol. 26; no. 1; pp. 110 - 121
• Main Authors: Liu, Jun, Huang, Kun, Cai, Guang-Yan, Chen, Xiang-Mei, Yang, Ju-Rong, Lin, Li-Rong, Yang, Jie, Huo, Ben-Gang, Zhan, Jun, He, Ya-Ni
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.01.2014
• Subjects: Activation; Age; Aged; Animals; Cells, Cultured; Cellular; Cellular Senescence - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; ER stress; Feedback, Physiological - drug effects; Glycation End Products, Advanced - pharmacology; Humans; Inducers; Kidney Tubules, Proximal - pathology; Mice; Middle Aged; p21; Positive feedback; Premature senescence; RAGE; Receptor for Advanced Glycation End Products; Receptors; Receptors, Immunologic - metabolism; Signal Transduction - drug effects; Stresses; 4-PBA; Premature senescence; MOI; GRP78; ER stress; DAPI; AGEs; DN; SAHF; RAGE; ER; p21; GFP; BSA; SA-β-gal; TG; TM; Diabetic nephropathy; PTECs; senescence-associated heterochromatic foci; 4-phenylbutyrate; advanced glycation end-products; multiplicity of infection; senescence-associated-β-galactosidase; glucose-regulated protein 78; 4′,6-diamidino-2-phenylindole; proximal tubular epithelial cells; Green fluorescent protein; thapsigargin; bovine serum albumin; endoplasmic reticulum; tunicamycin; receptor for advanced glycation end-products
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.10.002

Premature senescence is a key process in the progression of diabetic nephropathy (DN). In our study, we hypothesized that receptors for advanced glycation end-products (RAGE) mediate endoplasmic reticulum (ER) stress to induce premature senescence via p21 signaling activation in diabetic nephropathy. Here, we demonstrated that elevated expression of RAGE, ER stress marker glucose-regulated protein 78 (GRP78), and cell-cycle regulator p21 was all positively correlated with enhanced senescence-associated-β-galactosidase (SA-β-gal) activity in DN patients. In addition, the fraction of SA-β-gal or cells in the G0G1 phase were enhanced in cultured mouse proximal tubular epithelial cells (PTECs) and the expression of RAGE, GRP78 and p21 was up-regulated by advanced glycation end-products (AGEs) in a dose- and time-dependent manner. Interestingly, ER stress inducers or RAGE overexpression mimicked AGEs induced-premature senescence, and this was significantly suppressed by p21 gene silencing. However, RAGE blocking successfully attenuated AGEs-induced ER stress and p21 expression, as well as premature senescence. Moreover, ER stress inducers directly caused p21 activation, premature senescence, and also enhanced RAGE expression by positive feedback. These observations suggest that RAGE promotes premature senescence of PTECs by activation of ER stress-dependent p21 signaling. Note: We demonstrated that elevated expression of RAGE, GRP78 and p21 was all positively correlated with enhanced SA-β-gal activity in DN patients. In addition, the fraction of SA-β-gal or cells in the G0G1 phase were enhanced in cultured mouse PTECs; and the expression of RAGE, GRP78 and p21 was up-regulated by AGEs in a dose- and time-dependent manner. Interestingly, ER stress inducers or RAGE overexpression mimicked AGEs induced-premature senescence, and this was significantly suppressed by p21 gene silencing. However, RAGE blocking successfully attenuated AGEs induced ER stress and p21 expression, as well as premature senescence. Moreover, ER stress inducers directly cause p21 activation and premature senescence, and also enhanced RAGE expression via positive feedback. These observations suggest that RAGE promotes premature senescence of PTECs via activation of ER stress-dependent p21 signaling. [Display omitted] •RAGE and ER stress were positively correlated with premature senescence.•ER stress inducers or RAGE overexpression mimicked the premature senescence.•ER stress or RAGE inhibition led to reduction of p21 and premature senescence.•ER stress induced premature senescence by p21 signaling activation.