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Advanced glycation end product-induced proliferation in NRK-49F cells is dependent on the JAK2/STAT5 pathway and
1Department of Internal Medicine and School of Technology for Medical Science, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
Abstract:
Advanced glycation end products (AGEs) are important in the pathogenesis of diabetic nephropathy, which leads to renal fibrosis. Previously, we found that the janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway is necessary for AGE-induced cellular proliferation in normal rat kidney interstitial fibroblast (NRK-49F) cells. However, a direct link between JAK/STAT and cell-cycle progression has not been well established. In this regard, STAT5 has been found to induce cyclin D1 and proliferation in hematopoietic cells. Therefore, we examined effects of AGE on STAT5 and cell-cycle-dependent mitogenesis in NRK-49F cells. We found that AGE increased cyclin D1 expression and cyclin-dependent kinase (cdk)4 activity while decreasing p21(WAF1/CIP1) expression. We also found that AGE (100 microg/mL) induced STAT5 tyrosine phosphorylation. Meanwhile, AGE induced STAT5 protein-DNA binding activity, which was reversed by AG-490 (a specific JAK2 inhibitor) and STAT5 decoy oligodeoxynucleotide (ODN). In addition, STAT5 decoy ODN reversed AGE-induced cell-cycle-dependent cellular proliferation and cyclin D1 protein expression. We concluded that AGE induced cell-cycle-dependent cellular proliferation by inducing the JAK2-STAT5-cyclin D1 and cdk4 pathways in NRK-49F cells.
Insights
Advanced glycation end products (AGEs) drive diabetic nephropathy by activating the JAK2-STAT5 pathway, promoting kidney cell proliferation via cyclin D1 and CDK4. This research clarifies AGEs
Area of Science:
- Nephrology
- Cell Biology
- Endocrinology
Background:
- Advanced glycation end products (AGEs) are implicated in diabetic nephropathy pathogenesis.
- The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway is crucial for AGE-induced proliferation in kidney cells.
- A direct link between JAK/STAT signaling and cell-cycle progression in renal cells remains incompletely understood.
Purpose of the Study:
- To investigate the role of STAT5 in AGE-induced cell-cycle progression in normal rat kidney interstitial fibroblast (NRK-49F) cells.
- To elucidate the molecular mechanisms by which AGEs influence STAT5 activation and downstream cell-cycle regulatory proteins.
Main Methods:
- NRK-49F cells were treated with AGEs.
- STAT5 tyrosine phosphorylation, protein-DNA binding activity, cyclin D1 expression, and cell-cycle progression were assessed.
- Specific inhibitors (AG-490) and decoy oligodeoxynucleotides (ODN) targeting STAT5 were employed to probe pathway involvement.
Main Results:
- AGEs significantly increased cyclin D1 expression and cyclin-dependent kinase (cdk)4 activity.
- AGEs treatment led to increased STAT5 tyrosine phosphorylation and enhanced STAT5 protein-DNA binding activity.
- STAT5 decoy ODN effectively reversed AGE-induced cell-cycle progression and cyclin D1 expression, while AG-490 inhibited STAT5 activation.
Conclusions:
- AGEs induce cell-cycle-dependent cellular proliferation in NRK-49F cells.
- The JAK2-STAT5-cyclin D1 and cdk4 pathways are critical mediators of AGE-induced renal cell proliferation.
- Targeting the JAK2-STAT5 pathway may offer a therapeutic strategy for diabetic nephropathy.