Nifedipine, a calcium channel blocker, inhibits inflammatory and fibrogenic gene expressions in advanced glycation end product (AGE)-exposed fibroblasts via mineralocorticoid receptor antagonistic activity.
Advanced glycation end products (AGE) are involved in tissue damage and remodeling. This study investigated whether AGE could elicit inflammatory and fibrogenic reactions in fibroblast cell line MRC-5 cells via autocrine production of aldosterone and if nifedipine could block the AGE actions through mineralocorticoid receptor (MR) antagonistic activity. AGE significantly up-regulated monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta (TGF-beta), type III collagen and receptor for AGE (RAGE) mRNA levels in MRC-5 cells, all of which were completely blocked by nifedipine or an MR antagonist spironolactone. Aldosterone also dose-dependently increased MCP-1, TGF-beta and type III collagen mRNA levels in MRC-5 cells, which were suppressed by nifedipine, but not amlodipine, a control calcium channel blocker. Further, AGE significantly stimulated aldosterone generation in MRC-5 cells, which was partially blocked by nifedipine or spironolactone. In this study, we demonstrated for the first time that AGE could evoke inflammatory and fibrogenic reactions in MRC-5 cells via aldosterone production, which were blocked by the MR antagonistic activity of nifedipine. Our present study provides a unique beneficial aspect of nifedipine on tissue damage and remodeling; it could work as an anti-inflammatory and anti-fibrogenic agent against AGE via MR antagonistic activity.
Matsui
Takanori
T
Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
Takeuchi
Masayoshi
M
Yamagishi
Sho-ichi
S
D000450:Aldosterone / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D000451:Mineralocorticoid Receptor Antagonists; D009543:Nifedipine / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D017127:Glycation End Products, Advanced; D000451:Mineralocorticoid Receptor Antagonists; D000450:Aldosterone; D009543:Nifedipine