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Toshiki Nagasaki, Eiji Ishimura, Hidenori Koyama, Atsushi Shioi, Shuichi Jono, Masaaki Inaba, Tadayoshi Hasuma, Minehiko Yokoyama, Yoshiki Nishizawa, Hirotoshi Morii, Shuzo Otani, αv Integrin regulates TNF-α-induced nitric oxide synthesis in rat mesangial cells—possible role of osteopontin, Nephrology Dialysis Transplantation, Volume 14, Issue 8, August 1999, Pages 1861–1866, https://doi.org/10.1093/ndt/14.8.1861
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Abstract
Background. Tumour necrosis factor-α (TNF-α) induces nitric oxide (NO) synthesis in rat mesangial cells (MCs). We previously demonstrated that osteopontin (OP), a matrix protein that mainly interacts with theαv integrin family, increased time-dependently by TNF-α stimulation at gene and protein levels. The regulation of NO synthesis by integrins or matrixproteins is unclear.
Methods. We examined whether integrin, especiallyαv integrin, regulates NO synthesis in rat MCs and whether OP, anαv integrin ligand, has an effect on TNF-α-induced NO synthesis. Furthermore, OP and inducible NO synthase (iNOS) gene expression wasexamined by Northern blotting.
Results. TNF-α increased NO synthesis in MCs in a time-dependent manner. Synthetic GRGDSP peptide, whichis known to inhibit various integrins that interact with RGD-containing extracellular matrices,increased TNF-α-induced NO levels in a dose-dependent manner. Cyclical RGD peptide, the specific inhibitor ofαv integrin, also exhibited a dose-dependent effect of increasing NO levels, while GRGESP peptide,which has very low affinity to integrins, had no effect. In addition, NO synthesis was found to besignificantly reduced when MCs were plated on OP-coated dishes compared to type I or IVcollagen-coated dishes. Furthermore, anti-OP antibody increased NO synthesis in MCs. iNOSmRNA levels were increased by TNF-α, and were abruptly diminished after OP mRNA was significantly induced.
Conclusions. The present study demonstrated the involvement ofαv integrin in TNF-α-induced NO synthesis in rat MCs, and the possible role of OP was suggested in themechanism. TNF-α and extracellular matrices can co-operate to regulate the behaviour of MCs at least partlythrough NO synthesis, which may participate in the course of glomerular diseases.
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