Telmisartan but not valsartan inhibits TGF-β-mediated accumulation of extracellular matrix via activation of PPARγ

Abstract

Glomerulosclerosis, defined as phenotype transition of mesangial cell and deposition of extracelluar matrix, remains a chronic disease with excessive morbidity and mortality. The molecular mechanism underlying the suppression of mesangial cell activation is not fully understood. Since activation of peroxisome proliferators-activated receptor γ (PPARγ) has been proposed to decrease the effects of transforming growth factor-β (TGF-β) on glomerulosclerosis, we examined here whether and how telmisartan, an angiotensin II type 1 receptor blocker with PPARγ-modulating activity, inhibited TGF-β-induced glomerulosclerosis in rat glomerular mesangial cells. Protein levels of PPARγ were detected by Western blot. Activation of PPARγ response element (PPRE) was analyzed by luciferase assays. Deposition of extracelluar matrix was tested by confocol laser scanning. The results showed that telmisartan, but not valsartan, another angiotensin II type 1 receptor blocker, up-regulated PPARγ protein levels in a dose-dependent manner (P<0.05). Activation of PPRE, represented by luciferase activity, was also increased with higher concentration of telmisartan in a dose-dependent manner (P<0.05). Furthermore, telmisartan inhibited TGF-β-induced α-smooth muscle actin expression and collagen IV secretion in mesangial cells. GW9662, an inhibitor of PPAR-γ, blocked the inhibitory effects of telmisartan on TGF-β-induced glomerulosclerosis in mesangial cells. Our study indicates a benefit of telmisartan as a PPARγ agonist against TGF-β-induced mesangial cells activation in renal glomerulus. It may provide possibility that telmisartan works as a potential agent against diabetic nephropathy and hypertensive renal disease.

Keywords

telmisartan / glomerulosclerosis / peroxisome proliferators-activated receptor γ

References

[1] PadiyarA., SedorJ. R.. Genetic and genomic approaches to glomerulosclerosis. Curr Mol Med, 2005, 5(5): 497-507

[2] MakinoH.. Glomerular extracellular matrix in glomerulosclerosis by molecular biology. Nippon Rinsho, 1992, 50(12): 3038-3045

[3] ChenS., JimB., ZiyadehF. N.. Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol, 2003, 23(6): 532-543

[4] LibbyP., PlutzkyJ.. Inflammation in diabetes mellitus: role of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma agonists. Am J Cardiol, 2007, 99(4A): 27-40

[5] SharmaA. M., StaelsB.. Review: Peroxisome proliferator-activated receptor gamma and adipose tissue-understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab, 2007, 92(2): 386-395

[6] SpearsM., McsharryC., ThomsonN. C.. Peroxisome proliferator-activated receptor-gamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy, 2006, 36(12): 1494-1504

[7] GuytonK., BondR., ReillyC., et al.. Differential effects of 15-deoxy-delta(12,14)-prostaglandin J2 and a peroxisome proliferator-activated receptor gamma agonist on macrophage activation. J Leukoc Biol, 2001, 69(4): 631-638

[8] ZhengF., FornoniA., ElliotS. J., et al.. Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPARgamma activation. Am J Physiol Renal Physiol, 2002, 282(4): 639-648

[9] TaoL., LiuH. R., GaoE., et al.. Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia. Circulation, 2003, 108(22): 2805-2811

[10] IglesiasP., DiezJ. J.. Peroxisome proliferator-activated receptor gamma agonists in renal disease. Eur J Endocrinol, 2006, 154(5): 613-621

[11] BensonS. C., PershadsinghH. A., HoC. I., et al.. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension, 2004, 43(5): 993-1002

[12] FormanB. M., TontonozP., ChenJ., et al.. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell, 1995, 83(5): 803-812

[13] BrennerB. M., BeeuwkesR.3rd. The renal circulations. Hosp Pract, 1978, 13(7): 35-46

[14] HostetterT. H., OlsonJ. L., RennkeH. G., et al.. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J Am Soc Nephrol, 2001, 12(6): 1315-1325

[15] BrennerB. M.. Nephron adaptation to renal injury or ablation. Am J Physiol, 1985, 249(3Pt2): 324-337

[16] BrennerB. M.. Remission of renal disease: recounting the challenge, acquiring the goal.. J Clin Invest, 2002, 110(12): 1753-1758

[17] LiB., YaoJ., KawamuraK., et al.. Real-time observation of glomerular hemodynamic changes in diabetic rats: effects of insulin and ARB. Kidney Int, 2004, 66(5): 1939-1948

[18] KoboriH., Prieto-carrasqueroM. C., OzawaY., et al.. AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension. Hypertension, 2004, 43(5): 1126-1132

[19] SchuppM., JankeJ., ClasenR., et al.. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation, 2004, 109(17): 2054-2057

[20] ImayamaI., IchikiT., InanagaK., et al.. Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor gamma. Cardiovasc Res, 2006, 27(1): 184-190

[21] YoshidaT., YamagishiS., NakamuraK., et al.. Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation. Diabetologia, 2006, 49(12): 3094-3099

[22] SugimotoK., QiN. R., KazdovaL., et al.. Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension, 2006, 47(5): 1003-1009

[23] KurtzT. W.. Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. Acta Diabetol, 2005, 42(Suppl1): 9-16

[24] CybulskyA. V.. Growth factor pathways in proliferative glomerulonephritis. Curr Opin Nephrol Hypertens, 2000, 9(3): 217-223

[25] Morel-marogerS. L., KillenP. D., ChiE., et al.. The composition of glomerulosclerosis. I. Studies in focal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Lab Invest, 1984, 51(2): 181-192

[26] DongF. Q., LiH., CaiW. M., et al.. Effects of pioglitazone on expressions of matrix metalloproteinases 2 and 9 in kidneys of diabetic rats. Chin Med J (Engl), 2004, 117(7): 1040-1044

[27] ZafiriouS., StannersS. R., SaadS., et al.. Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. J Am Soc Nephrol, 2005, 16(3): 638-645