Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells

Abstract

Advanced glycation end-product (AGE) is important in the pathogenesis of diabetic nephropathy (DN), and captopril (an angiotensin converting enzyme inhibitor) is effective in treating this disorder. We have shown that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade is responsible for AGE-induced mitogenesis in NRK-49F (normal rat kidney fibroblast) cells, but its role in renal fibrosis in DN remains unknown. Therefore, we have sought to determine whether JAK/STAT is involved in AGE-regulated collagen production in NRK-49F cells. We found that AGE time (1-7 days) and dose (10-200 microg/ml)-dependently increased collagen production in these cells. Additionally, AGE increased RAGE (receptor for AGE) protein expression. AGE-induced RAGE expression was dose-dependently inhibited by antisense RAGE oligodeoxynucleotide (ODN) and captopril. AGE-induced type I collagen production and JAK2-STAT1/STAT3 activation were decreased by AG-490 (a specific JAK2 inhibitor), antisense RAGE ODN and captopril. Meanwhile, STAT1 and STAT3 decoy ODNs also suppressed the induction of collagen by AGE. We concluded that RAGE and the JAK2-STAT1/STAT3 pathway were involved in AGE-induced collagen production in NRK-49F cells. Furthermore, captopril was found to reverse AGE-induced collagen production, probably by attenuating RAGE expression and JAK2-STAT1/STAT3 activities.

Effect of Nitric Oxide-cGMP-Dependent Protein Kinase Activation on Advanced Glycation End-Product–Induced Proliferation in Renal Fibroblasts

“…Type IV collagen is transcriptionally regulated by Smad1 under AGE stimulation in mesangial cells (47). Interestingly, our previous studies showed that RAGE and the JAK2-STAT1/ STAT3 pathway were involved in AGE-induced collagen production in NRK-49F cells (48). Furthermore, in this study, we found that p42/p44 MAPK activity was increased in AGEtreated cells, but this activity was unaffected by SNAP, SNP, and 8-pCPT-cGMP.…”

Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts

“…15 Control solutions always contained an appropriate amount (Ͻ1:1000 dilution for each) of vehicle: ethanol for aldosterone (Across Organics), DMSO for eplerenone (Pfizer Inc) and PD98059 (Merck KGaA), and distilled water for cycloheximide (Sigma Chemical Co). At subconfluence, the culture medium was replaced with serum-free medium for 24 to 30 hours to render the cells quiescent.…”

Inhibitory effect of receptor for advanced glycation end products (RAGE) on the TGF-β-induced alveolar epithelial to mesenchymal transition

“…RAGE expression increases whenever its ligands accumulate, and the interaction of RAGE with its ligand promotes the progression of several non-pulmonary diseases, including diabetic nephropathy, diabetic atherosclerosis, and neurodegenerative disorders (Brownlee et al, 1988;Schmidt et al, 2000Schmidt et al, , 2001Morcos et al, 2002). The binding of AGE, S100/calgranulins, and HMGB1 to RAGE on vascular endothelial cells, neuronal cells, smooth muscle cells, or inflammatory cells may activate a range of signaling pathways, including those involving ERK1/2 MAP kinase, p38 and SAPK/JNK MAP kinase, rho GTPase, PI-3 kinase, and JAK/STAT, as well as the downstream activation of NF-kB (Kislinger et al, 1999;Huang et al, 2001;Yeh et al, 2001).…”