Skip to main content

Advertisement

Log in

Antiproliferative effect of fluvastatin and thiazolidinedione in mesangial cells of diabetic rats

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Treatment with hydroxymethylglutaryl coenzyme A reductase inhibitors and thiazolidinedione derivatives may prevent the development of diabetic nephropathy. The precise mechanisms of the beneficial effects of these agents in mesangial cells are uncertain. We cultured mesangial cells from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for human type 2 diabetes mellitus. The effects of fluvastatin and/or troglitazone on DNA synthesis were determined. Fluvastatin in combination with troglitazone markedly inhibited DNA synthesis and induced apoptosis in mesangial cells from OLETF rats. Combined therapy with fluvastatin and thiazolidinedione derivatives may be effective for suppression of mesangial cell proliferation in the early phase of diabetes, thereby possibly slowing the evolution of diabetic glomerulopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6A–C

Similar content being viewed by others

References

  1. Rate R, Knowler C, Morse H, Bonnell MD, McVey J, Chervenak CL, Smith MG, Pavanich G (1983) Diabetes mellitus in Hopi and Navajo Indians. Diabetes 32:894–899

    CAS  PubMed  Google Scholar 

  2. Collins A, Hanson G, Umen A, Kjellstrand C, Keshaviah P (1990) Changing risk factor demographics in end-stage renal disease patients entering hemodialysis and the impact on long-term mortality. Am J Kidney Dis 15:422–432

    CAS  PubMed  Google Scholar 

  3. Perneger T, Brancati F, Whelton P, Klag (1994) End-stage renal disease attributable to diabetes mellitus. Ann Intern Med 121:912–918

    CAS  PubMed  Google Scholar 

  4. Flyvjerg A, Gronbaek H, Bak, Nielsen B, Christiansen T, Hill C, Logan A, Orskov H (1998) Diabetic kidney disease: the role of growth factors. Nephrol Dial Transplant 13:1104–1107

    Article  PubMed  Google Scholar 

  5. Kikkawa R, Haneda (1997) Pathogenesis of diabetic nephropathy. Clin Exp Nephrol 1:3-11

    CAS  Google Scholar 

  6. Wolf G, Ziyadeh F (1999) Molecular mechanisms of diabetic renal hypertrophy. Kidney Int 56:393–405

    Article  CAS  PubMed  Google Scholar 

  7. Mahadevan P, Larkins R, Fraser J, Dunlop M (1996) Effect of prostaglandin E2 and hyaluronan on mesangail cell proliferation: a potential contribution to glomerular hypercellularity in diabetes. Diabetes 45:44–50

    CAS  PubMed  Google Scholar 

  8. Nakamura T, Sekino K, Ishii F, Kudoo M, Imamura K, Kikuchi N, Takebe T (1993) mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 42:450–456

    CAS  PubMed  Google Scholar 

  9. Shankland S, Scholey J, Ly H, Thai (1995) Expression of growth-related protooncogenes during diabetic renal hypertrophy. Kidney Int 47:782–788

    CAS  PubMed  Google Scholar 

  10. Young BA, Johnson RJ, Alpers CE, Eng E, Gordon K, Floege J, Couser WG, Seidel K (1995) Cellular events in the evolution of experimental diabetic nephropathy. Kidney Int 47:935–944

    CAS  PubMed  Google Scholar 

  11. Ayo S, Radnik R, Garoni J, Glass W, Kreisberg J (1990) High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells. Am J Pathol 136:1339–1348

    CAS  PubMed  Google Scholar 

  12. Wolf G, Sharma K, Chen Y, Ericksen M, Ziyadeh F (1992) High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-beta. Kidney Int 42:647–656

    CAS  PubMed  Google Scholar 

  13. Okada M, Takemura T, Hino S, Yanagida H, Yoshioka K (1997) Cell proliferation, extracellular matrix (ECM) production and sensitivity to angiotensin II (AII) in mesangial cell of spontaneous long-term hyperglycemic (OLETF) rat with diabetic complications (abstract). J Am Soc Nephrol 8:644A

    Google Scholar 

  14. Yanagida H, Takemura T, Okada M, Hino S, Ikeda M, Yoshioka K (1998) Functional response to low density lipoprotein (LDL) in mesangial cells of diabetic rats (abstract). J Am Soc Nephrol 9:644A

    Google Scholar 

  15. Kawano K, Hirashima T, Mori S, Kurosumi M, Saitoh Y (1991) A new rat strain with non-insulin dependent diabetes mellitus, OLETF Rat. News Lett 25:24–26

    Google Scholar 

  16. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T (1992) Spontaneous long-term hyperglycemic rat with diabetic complications; Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41:1422–1428

    CAS  PubMed  Google Scholar 

  17. Miyazato H, Takemura T, Hino S, Yagi K, Fukushima K, Yoshioka K (1998) Glucocorticoid-induced apoptosis of rat mesangial cells in culture. Clin Exp Nephrol 2:12–17

    CAS  Google Scholar 

  18. Takemura T, Murata Y, Hino S, Okada M, Yanagida H, Ikeda M, Yoshioka K (1999) Heparin-binding EGF-like growth factor is expressed by mesangial cells and involved in mesangial proliferation in glomerulonephritis. J Pathol 189:431–438

    Article  CAS  PubMed  Google Scholar 

  19. Takemura T, Kondo S, Homma T, Sakai M, Harris R (1997) The membrane-bound form of heparin-binding epidermal growth factor-like growth factor promotes survival of cultured renal epithelial cells. J Biol Chem 272:31036–31042

    Article  CAS  PubMed  Google Scholar 

  20. Takemura T, Hino H, Murata Y, Yanagida H, Okada M, Yoshioka K, Harris RC (1999) Coexpression of CD9 augments the ability of membrane-bound heparin-binding epidermal growth factor-like growth factor (proHB-EGF) to preserve renal epithelial cell viability. Kidney Int 55:71–81

    Article  CAS  PubMed  Google Scholar 

  21. Takemura T, Yoshioka K, Murakami K, Akano N, Okada M, Aya N, Maki S (1994) Cellular localization of inflammatory cytokines in human glomerulonephritis. Virchows Arch 424:459–464

    CAS  PubMed  Google Scholar 

  22. Yoshioka K, Takemura T, Murakami K, Okada M, Hino S, Miyazato H, Maki S (1993) Transforming growth factor-b protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest 68:154–163

    CAS  PubMed  Google Scholar 

  23. Osterby R (1972) Morphological studies of the peripheral glomerular basement membrane in early juvenile diabetes. I. Development of initial basement membrane thickening. Diabetologia 8:84–92

    CAS  PubMed  Google Scholar 

  24. Osterby R, Gundersen H (1975) Glomerular size and structure in diabetic mellitus. I. Early abnormalities. Diabetologia 11:225–229

    CAS  PubMed  Google Scholar 

  25. Seyer-Hansen K (1976) Renal hypertrophy in streptozotocin-diabetic rats. Clin Sci Mol Med 51:551–555

    CAS  Google Scholar 

  26. Romen W, Takahashi A (1982) Autoradiographic studies on the proliferation of glomerular and tubular cells of rat kidney in early diabetes. Virchows Arch [B] 40:339–345

  27. Jerums G, Allen TJ, Tsalamandris C, Akdeniz A, Sinha A, Gilbert R, Cooper ME (1993) Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetic patients. Diabetologia 36:1037–1044

    CAS  PubMed  Google Scholar 

  28. Diamond J, Karnovsky M (1987) Exacerbation of chronic aminonucleoside nephrosis by dietary cholesterol supplementation. Kidney Int 32:671–678

    CAS  PubMed  Google Scholar 

  29. Kasiske B, Cleary M, O′Donnell M, Keane W (1988) Mechanisms of glomerular injury in the obese Zucker rat. Kidney Int 33:667–672

    CAS  PubMed  Google Scholar 

  30. Grone H-J, Walli A, Grone E, Kramer A, Clemens M, Seidel D (1990) Receptor mediated uptake of apo B and apo E rich lipoproteins by human glomerular epithelial cells. Kidney Int 37:1449–1459

    CAS  PubMed  Google Scholar 

  31. Wesserman J, Santiago A, Rifici V, Holthofer H, Scharschmidt L, Epstein M, Schlondorff D (1989) Interactions of low density lipoprotein with rat mesangial cells. Kidney Int 35:1168–1174

    PubMed  Google Scholar 

  32. Jandeleit-Dahm K, Cao Z, Cox A, Kelly D, Gilbert R, Cooper M (1999) Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. Kidney Int 56: S31–S36

    Article  Google Scholar 

  33. Kasiske B, O′Donnell M, Garvis W, Keane W (1988) Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ Res 62:367–374

    CAS  PubMed  Google Scholar 

  34. Muso E, Yashiro M, Matsushima M, Yoshida H, Sawanishi K, Sasayama S (1994) Does LDL-apheresis in steroid-resistant nephrotic syndrome affect prognosis? Nephrol Dial Transplant 9:257–264

    CAS  PubMed  Google Scholar 

  35. Hussein O, Schlezinger S, Rosenblat M, Keidar S, Aviram M (1997) Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypochoresterolemic effect of the drug and its binding to the LDL. Atherosclerosis 128:11–18

    Article  CAS  PubMed  Google Scholar 

  36. Jacotot B, Benghozi R, Pfister P, Holmes D, French Fluvastatin Study Group (1995) Comparison of fluvastatin and pravastatin treatment of primary hypercholesterolemia. Am J Cardiol 76:54A

    CAS  PubMed  Google Scholar 

  37. Schulte K-L, Beil S (1996) Efficacy and tolerability of fluvastatin and sinvastatin in hypercholesterolemic patients: a double blind, randomized, parallel-group comparison. Clin Drug Invest 12:119–126

    CAS  Google Scholar 

  38. O′Donnell M, Kasiske B, Kim Y, Atluru D, Keane W (1993) Lovastatin inhibits proliferation of rat mesangial cells. J Clin Invest 91:83–87

    CAS  PubMed  Google Scholar 

  39. Quesney-Huneeus V, Wiley M, Siperstein M (1979) Essential role of mevalonate synthesis in DNA replication. Proc Natl Acad Sci U S A 76:5056–5060

    CAS  PubMed  Google Scholar 

  40. Massy Z, Guijarro C, O′Donnell M, Kasiske B, Keane W (1997) Regulation of mesangial cell proliferation by the mevalonate pathway. Contrib Nephrol 120:191–196

    CAS  PubMed  Google Scholar 

  41. Grandaliano G, Biswas P, Choudhury G, Abboud H (1993) Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Kidney Int 44:503–508

    CAS  PubMed  Google Scholar 

  42. Baetta R, Donetti E, Comparato C, Calore M, Rossi A, Teruzzi C, Paoletti R, Fumagalli R, Soma MR (1997) Proapoptotic effect of atorvastatin on stimulated rabbit smooth muscle cells. Pharmacol Res 36:115–121

    Article  CAS  PubMed  Google Scholar 

  43. Buemi M, Allegra A, Senatore M, Marino D, Medici MA, Aloisi C, Di Pasquale G, Corica F (1999) Pro-apoptotic effect of fluvastatin on human smooth muscle cells. Eur J Pharmacol 370:201–203

    Article  CAS  PubMed  Google Scholar 

  44. Korsmeyer S (1992) Bcl-2: a repressor of lymphocyte death. Immunol Today 13:285–288

    Article  CAS  PubMed  Google Scholar 

  45. Takemura T, Murakami K, Miyazato H, Yagi K, Yoshioka K (1995) Expression of Fas antigen and Bcl-2 in human glomerulonephritis. Kidney Int 48:1886–1892

    CAS  PubMed  Google Scholar 

  46. Hayashi K, Kurokawa J, Nomura S, Kuga Y, Ohkura Y, Kajiyama G (1993) Effect of fluvastatin sodium (XU 62–320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the induction of low-density lipoprotein receptor in HepG2 cells. Biochem Biophys Acta 1167:223–225

    Article  CAS  PubMed  Google Scholar 

  47. Hofmann C, Colca J (1992) New oral thiazolidinedione antidiabetic agents act as insulin sensitizers. Diabetes Care 15:1075–1078

    CAS  PubMed  Google Scholar 

  48. Lehman J, Moore L, Smith-Oliver T, Wilkinson W, Wilson T, Kliewer S (1995) An antidiabetic thiazolidinedione is the high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270:12953–12956

    CAS  PubMed  Google Scholar 

  49. Hallakou S, Doare L, Foufelle D, Kergoat M, Guerre-Millo M, Berthault MF, Dugail I, Morin J, Auwerx J, Ferre P (1997) Pioglitazone induces in vitro adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 46:1393–1399

    CAS  PubMed  Google Scholar 

  50. Spiegelman B (1998) PPAR-g; adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514

    CAS  PubMed  Google Scholar 

  51. Graf K, Xi X, Hsueh W, Law R (1997) Troglitazone inhibits angiotensin II-induced DNA synthesis and migration in vascular smooth muscle cells. FEBS Lett 400:119–121

    Article  CAS  PubMed  Google Scholar 

  52. Yasurari K, Kohno M, Kano H, Yokokawa K, Minami M, Yoshikawa J (1997) Mechanisms of action of troglitazone in the prevention of high glucose-induced migration and proliferation of cultured coronary smooth muscle cells. Circ Res 81:953–962

    PubMed  Google Scholar 

  53. Fujii M, Takemura R, Yamaguchi M, Hasegawa G, Shigeta H, Nakano K, Kondo M (1997) Troglitazone (CS-045) ameliorates albuminuria in streptozotocin-induced diabetic rats. Metabolism 46:981–983

    CAS  PubMed  Google Scholar 

  54. Iwano E, Motomura M, Kanda (1998) Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Care 21:2135–2139

    PubMed  Google Scholar 

  55. Isshiki K, Haneda M, Koya D, Hayashi K, Kikkawa R (2000) Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats. Diabetes 49:1022–1032

    CAS  PubMed  Google Scholar 

  56. McCarthy K, Earl R, Shaw R, Walsh K, Welbourne T, Johnson J (2000) Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion. Kidney Int 58:2341–2350

    Article  CAS  PubMed  Google Scholar 

  57. Nagasaka Y, Kaku K, Nakamura K, Kaneko T (1995) The new oral hypoglycemic agent, CS-045, inhibits the lipid peroxidization of human plasma low density lipooprotein in vitro. Biochem Pharmacol 50:1109–1111

    Article  CAS  PubMed  Google Scholar 

  58. Wheeler D, Persaud J, Fernando R, Sweny P, Varghese Z, Moorhead J (1990) Effects of low-density lipoproteins on mesangial cell growth and viability in vitro. Nephrol Dial Transplant 5:185–191

    CAS  PubMed  Google Scholar 

  59. Jiang C, Ting A, Seed B (1998) PPAR-g agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82–86

    CAS  PubMed  Google Scholar 

  60. Elstner E, Muller C, Koshizuka K, Willamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP (1998) Ligands for peroxisome proliferator-activated receptor gamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A 95:8806–8811

    CAS  PubMed  Google Scholar 

  61. Hirase N, Yanase T, Mu Y, Muta K, Uemura T, Takayanagi R, Nawata H (1999) Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60. Oncology 57 [Suppl 2]:17–26

  62. Takahashi N, Okumura T, Motomura W, Fujimoto Y, Kawabata I, Kohgo Y (1999) Activation of PPAR gamma inhibits cell growth and induces apoptosis in human gastric cancer cells. FEBS Lett 455:135–139

    CAS  PubMed  Google Scholar 

  63. Jenkins A, Velarde V, Klein R, Joyce KC, Phillips KD, Mayfield RK, Lyons TJ, Jaffa AA (2000) Native and modified LDL activate extracellular signal-regulated kinases in mesangial cells. Diabetes 49:2160–2169

    CAS  PubMed  Google Scholar 

  64. Kikkawa R, Umehara K, Haneda M, Arimura T, Ebata K, Shigeta Y (1987) Evidence for existence of polyol pathway in cultured rat mesangial cells. Diabetes 36:240–243

    CAS  PubMed  Google Scholar 

  65. Kikkawa R, Umehara K, Haneda M, Kajiwara N, Maeda S, Nishimura C, Shigeta Y (1992) Identification and characterization of aldose reductase in cultured rat mesangial cells. Diabetes 41:1165–1171

    CAS  PubMed  Google Scholar 

  66. Imura H (1998) A novel antidiabetic drug, troglitazone—reason for hope and concern. N Engl J Med 26:908–909

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from Morinaga Hohshikai, Japan (to M.O., AA03979) and a grant from Osaka Kidney Foundation, Japan (to M.O., OKF00–001).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tsukasa Takemura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okada, M., Yanagida, H., Kuwajima, H. et al. Antiproliferative effect of fluvastatin and thiazolidinedione in mesangial cells of diabetic rats. Pediatr Nephrol 19, 26–32 (2004). https://doi.org/10.1007/s00467-003-1306-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-003-1306-y

Keywords

Navigation