Original Article | Published:

Endocrine Pharmacology

Effect of telmisartan on expression of protein kinase C-α in kidneys of diabetic mice

Acta Pharmacologica Sinica volume 28, pages 829838 (2007) | Download Citation

Project supported by funds from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (No 2005-21).

Abstract

Aim:

To investigate the effects of angiotensin receptor blocker (ARB) telmisartan on the expression and distribution of protein kinase C (PKC)-α in the kidneys of diabetic mice.

Methods:

Diabetic mice were induced with streptozotocin and a group of them were randomly selected for treatment with telmisartan. After 6 weeks, the expression and localization of PKC-α in the renal cortex, and the outer and inner medulla were assessed by immunohistochemistry and semiquantitative Western blotting. In addition, expressions of PKC-α, transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor (VEGF) in glomeruli were measured by semiquantitative immunohistochemistry.

Results:

Diabetic and normal mice showed similar distributions of PKC-α in the kidneys. The expression of PKC-α was found in glomeruli, epithelial cells of proximal tubules, and medullary-collecting duct, while not in the medullary and cortical thick ascending limb, and was different in the epithelial cells of proximal tubules of diabetic nephropathy (DN) mice, PKC-α was mostly translocated from the basement membrane to the apical membrane, whereas it was largely translocated from the apical membrane to the basement membrane in epithelial cells of the inner medullary-collecting duct. Western blotting detected increased expression of PKC-α in the renal cortex and outer medulla, but not in the inner medulla of DN mice. Enhanced expressions of PKC-α, TGF-β1, and VEGF were shown in the glomeruli of DN mice, where PKC-α exhibited a correlation to VEGF, but no correlation to TGF-β1. ARB telmisartan attenuated alterations of PKC-α as mentioned earlier in the DN mice.

Conclusion:

Our findings suggest that PKC-α may play a role in the pathogenesis of DN, and that the nephroprotective effects of ARB telmisartan may be partly associated with its influence on PKC-α.

References

  1. 1.

    . Biochemistry and molecular cell biology of diabetic complications. Nature, 2001; 414: 813–20.

  2. 2.

    . Postprandial glucose and vascular disease. Diabet Med, 1997; 14: S50–6.

  3. 3.

    , . Protein kinase C activation and its pharmacological inhibition in vascular disease. Vasc Med, 2000; 5: 173–85.

  4. 4.

    , , , , , et al. Differential expression of protein kinase C isoforms in streptozotocin-induced diabetic rats. Kidney Int, 1999; 56: 1737–50.

  5. 5.

    , , , , , et al. Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway. Diabetes, 2004; 53: 2921–30.

  6. 6.

    , , , , , et al. Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-α-deficient diabetic mice. Diabetes, 2004; 53: 2101–9.

  7. 7.

    , , , , , . Evidence for a role of protein kinase C alpha in urine concentration. Am J Physiol Renal Physiol, 2004; 287: F299–304.

  8. 8.

    , , , , , . The key role of the transforming growth factor-β system in the pathogenesis of diabetic nephropathy. Ren Fail, 2001; 23: 471–81.

  9. 9.

    , , . From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes, 2005; 54: 1626–34.

  10. 10.

    , , . Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol, 2003; 23: 532–43.

  11. 11.

    , , , , , . Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol, 2001; 12: 993–1000.

  12. 12.

    , , , , , . Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes, 2002; 51: 3090–4.

  13. 13.

    , , . The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int, 2004; 65: 2003–17.

  14. 14.

    , , , , , et al. Role of vascular endothelial growth factor in diabetic nephropathy. Kidney Int Suppl, 2000; 77: S104–12.

  15. 15.

    , , , . Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 1997; 46: 1497–503.

  16. 16.

    , , , , . High glucose induced VEGF expression via PKC and ERK in glomerular podocytes. Biochem Biophys Res Commun, 2002; 290: 177–84.

  17. 17.

    , , , , , et al. Glucose-induced TGF-β1 and TGF-β receptor-1 expression in vascular smooth muscle cells is mediated by protein kinase C-α. Hypertension, 2003; 42: 335–41.

  18. 18.

    , , , , . PKC- and MAPK-independent upregulation of VEGF receptor expressions in human umbilical venous endothelial cells following VEGF stimulation. Hepatol Res, 2001; 21: 261–7.

  19. 19.

    . New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest, 2004; 34: 785–96.

  20. 20.

    , , , , , et al. The telmisartan renoprotective study from incipient nephropathy to overt nephropathy-rationale, study design, treatment plan and baseline characteristics of the incipient to overt: angiotensin II receptor blocker, telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) Study. J Int Med Res, 2005; 33: 677–86.

  21. 21.

    , , , . Comparative antihypertensive and renoprotective effects of telmisartan and lisinopril after long-term treatment in hypertensive diabetic rats. J Renin Angiotensin Aldosterone Syst, 2001; 2: 31–6.

  22. 22.

    , , , . Immunolocalization of protein kinase C isoenzymes α, βI, βII, δ, and ζ in mouse kidney. Am J Physiol Renal Physiol, 2004; 287: 289–98.

  23. 23.

    , , . Immunolocalization of protein kinase C isoenzymes α, βI and βII in rat kidney. J Am Soc Nephrol, 1999; 10: 1861–73.

  24. 24.

    . Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science, 1992; 258: 607–14.

  25. 25.

    , , , . Protein kinase C isoforms in rat kidney proximal tubule: acute effect of angiotensin II. Am J Physiol Cell Physiol, 1995; 269: 134–40.

  26. 26.

    , , , . Parathyroid hormone-mediated regulation of Na+-K+-ATPase requires ERK-dependent translocation of protein kinase Calpha. J Biol Chem, 2005; 280: 8705–13.

  27. 27.

    , . Nitric oxide activates PKC-alpha and inhibits Na+-K+-ATPase in opossum kidney cells. Am J Physiol, 1999; 277: F859–65.

  28. 28.

    , , , , . Endogenous digitalis-like ligands and Na/K-ATPase inhibition in experimental diabetes mellitus. Front Biosci, 2005; 10: 2257–62.

  29. 29.

    , , . PKC-alpha-mediated remodeling of the actin cytoskeleton is involved in constitutive albumin uptake by proximal tubule cells. Am J Physiol Renal Physiol, 2005; 288: F1227–35.

  30. 30.

    , , , , . Angiotensin II promotes glucose-induced activation of cardiac protein kinase C isozymes and phosphorylation of troponin I. Diabetes, 2001; 50: 1918–26.

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Author information

Affiliations

  1. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

    • Li-jun Yao
    • , Jian-qing Wang
    • , Jian-she Liu
    •  & An-guo Deng
  2. Department of Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China

    • Hong Zhao

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Corresponding author

Correspondence to Li-jun Yao.

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DOI

https://doi.org/10.1111/j.1745-7254.2007.00541.x

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