Downregulation of p38 MAPK involved in inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin

Abstract

Curcumin, as a main pharmacological component in the traditional Chinese medicine—turmeric, has shown anti-inflammatory, anti-oxidation, anti-tumor and anti-fibrotic effects. This study aimed to investigate the possible underlying signaling pathway which was involved in the inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin. Rat mesangial cells in vitro were incubated with low-density lipoprotein (LDL) and different concentrations of curcumin (0, 6.25, 12.5, 25.0 μmol/L) or p38 MAPK inhibitor, SB203580 (10 μmol/L). Under LDL incubation, mesangial cells proliferated, the expression of MMP-2 mRNA and protein was decreased, the expression of COX-2 mRNA and protein was increased, reactive oxygen species (ROS) generation was increased and p38 MAPK was activated significantly (P<0.05). When LDL-induced cells were treated with curcumin in the concentration of 12.5 or 25.0 μmol/L, LDL-induced proliferation of mesangial cells was suppressed, the expression of MMP-2 mRNA and protein increased, the expression of COX-2 mRNA and protein downregulated, the production of ROS inhibited and p38 MAPK inactivated (P<0.05). In conclusion, curcumin can inhibit the LDL-induced proliferation of mesangial cells and up-regulate the expression of MMP-2, which may be related with the inhibitory effect of curcumin on COX-2 expression, ROS production and p38 MAPK.

Keywords

curcumin / low-density lipoprotein / reactive oxygen species / cyclooxygenase-2 / p38 mitogen activated protein kinase

References

[1] TianW, ZhangZ, CohenDM. MAPK signaling and the kidney. Am J Physiol Renal Physiol, 2000, 279(4): F593-F604

[2] ShahedAR, JonesE, ShoskesD. Quercetin and curcumin up-regulate antioxidant gene expression in rat kidney after ureteral obstruction or ischemia/reperfusion injury. Transplant Proc, 2001, 33(6): 2988

[3] GaertnerSA, JanssenU, OstendorfT, et al.. Glomerular oxidative and antioxidative systems in experimental mesangioproliferative glomerulonephritis. J Am Soc Nephrol, 2002, 13(12): 2930-2937

[4] IshaqueA, DunnMJ, SorokinA. Cyclooxygenase-2 inhibits tumor necrosis factor alpha-mediated apoptosis in renal glomerular mesangial cells. J Biol Chem, 2003, 278(12): 10 629-10 640

[5] MiyataY, KogaS, KandaS, et al.. Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival. Clin Cancer Res, 2003, 9(5): 1741-1749

[6] ChenHC, GuhJY, ShinSJ, et al.. Pravastatin suppress superoxide and fibronectin production of glomerular mesangial cells induced by oxidized-LDL and high glucose. Atherosclerosis, 2002, 160(1): 141-146

[7] LeeHB, YuMR, YangY, et al.. Reactive oxygen species-regulated signaling pathways in diabetic nephropathy. J Am Soc Nephrol, 2003, 14(8Suppl3): S241-S245

[8] AhmadM, TheofanidisP, MedfordRM. Role of activating protein-1 in the regulation of the vascular cell adhesion molecule-1 gene expression by tumor necrosis factor-alpha. J Biol Chem, 1998, 273(8): 4616-4621

[9] BalasubramanyamM, KoteswariAA, KumarRS, et al.. Curcumin-induced inhibition of cellular reactive oxygen species generation: novel therapeutic implications. J Biosci, 2003, 28(6): 715-721

[10] IqbalM, OkazakiY, OkadaS. In vitro curcumin modulates ferric nitrilotriacetate (Fe-NTA) and hydrogen peroxide (H₂O₂)-induced peroxidation of microsomal membrane lipids and DNA damage. Teratog Carcinog Mutagen, 2003151-160