LDL receptor gene expression in human mesangial cells under the influence of calcium channel blockers

Background: Intracellular transport of lipid through the regulation of LDL receptor (LDLr) may be important in the progression of renal dysfunction. M ethods: We explored LDLr gene expression in human mesangial cell line (HMCL ) under influence of calcium channel blockers using cell proliferation, LDL binding, Northern blot and LDLr promoter activity assay. Results: Diltiaze m and verapamil increased the expression of LDLr mRNA in a dose-dependent m anner. Increased LDLr mRNA paralleled LDL binding. Nifedipine did not incre ase the expression of LDLr mRNA and LDL binding to HMCL at 1 - 100 mu mol/l . The LDLr promoter activity assay showed that treatment with 100 mu mol/l of diltiazem and verapamil increased LDLr promoter activity by 126.72 +/- 1 0.68%, and 166.41 +/- 11.41%, respectively, at 24 hours (control as 100%), while treatment with 100 mu mol/l of nifedipine had an inhibitory effect on LDLr promoter activity. High concentration of LDL (250 mu g/ml) inhibited promoter activity. Diltiazem or verapamil coincubated with LDL (250 mu g/ml ) could not override transcriptional inhibition by LDL. CCBs inhibited the proliferation of HMCL, therefore, CCBs-induced LDLr expression did not depe nd on a proliferative response. Signal transduction pathway experiments sho wed that the calmodulin transduction pathway was involved in LDLr upregulat ion induced by diltiazem or verapamil. Additionally, tyrosine kinase and PK C pathways were involved in the induction of LDLr induced by verapamil. Con clusion: These studies show that diltiazem and verapamil increase LDLr gene transcription and expression which is independent of cell proliferation in HMCL.