Skip to main content
SpringerLink
Log in

Peroxynitrite mediates glomerular lesion of diabetic rat via JAK/STAT signaling pathway

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background: Peroxynitrite, a highly reactive oxidant produced by the reaction of nitric oxide with free radicals superoxide, has been indicated to be involved in many diseases. However, the contributions of peroxynitrite to diabetic nephropathy and the underlying mechanism have not been fully explored. Aim: The present study was designed to evaluate the role and the underlying mechanism of peroxynitrite in glomerular lesion of diabetic rat. Methods: Diabetes was induced in male Wistar rats by ip injection of streptozotocin, and urate was used as a specific scavenger of peroxynitrite; the pathological changes of rat glomerulus were evaluated by hematoxylin and eosin, periodic acid-Schiff staining and transmission electron microscopy observation; immunohistochemistry and Western blot were used to detect the content of nitrotyrosine (the marker of peroxynitrite) in renal cortex; the expression levels of tyrosine phosphorylation of JAK2, STAT1, and STAT3 were assessed by Western blot assay; RT-PCR and Western blot were used to assay expression levels of transforming growth factor (TGF)-β1 and fibronectin; biochemical indicators of renal function were also detected. Results: The content of nitrotyrosine was increased, consistent with the pathological changes of glomerulus and renal dysfunction in the diabetes group. Urate prevented the formation of nitrotyrosine in rat glomerulus and attenuated the pathological alterations. Furthermore, urate inhibited the activation of JAK2, STAT1, and STAT3. Finally, homogenates from renal cortices demonstrated reduced expression of TGF-β1 and fibronectin under urate treatment. Conclusions: Our findings thus provides in vivo evidence that exaggerated peroxynitrite formation mediates the glomerular lesion in, at least, Type 1 diabetes, which may function through JAK/STAT signaling pathway.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci USA 2007, 104: 3432–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Pop-Busui R, Sima A, Stevens M. Diabetic neuropathy and oxidative stress. Diabetes Metab Res Rev 2006, 22: 257–73.

    Article  CAS  PubMed  Google Scholar 

  3. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation 2003, 108: 2034–40.

    Article  PubMed  Google Scholar 

  4. Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 2004, 25: 612–28.

    Article  CAS  PubMed  Google Scholar 

  5. Shah SV, Baliga R, Rajapurkar M, Fonseca VA. Oxidants in chronic kidney disease. J Am Soc Nephrol 2007, 18: 16–28.

    Article  CAS  PubMed  Google Scholar 

  6. Kaniuk NA, Kiraly M, Bates H, Vranic M, Volchuk A, Brumell JH. Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes 2007, 56: 930–9.

    Article  CAS  PubMed  Google Scholar 

  7. Ali TK, Matragoon S, Pillai BA, Liou GI, El-Remessy AB. Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes. Diabetes 2008, 57: 889–98.

    Article  CAS  PubMed  Google Scholar 

  8. Obrosova IG, Mabley JG, Zsengellér Z, et al. Role for nitrosative stress in diabetic neuropathy: evidence from studies with a peroxynitrite decomposition catalyst. FASEB J 2005, 19: 401–3.

    CAS  PubMed  Google Scholar 

  9. van der Vliet A, Hristova M, Cross CE, Eiserich JP, Goldkorn T. Peroxynitrite induces covalent dimerization of epidermal growth factor receptors in A431 epidermoid carcinoma cells. J Biol Chem 1998, 273: 31860–6.

    Article  PubMed  Google Scholar 

  10. Clavreul N, Adachi T, Pimental DR, Ido Y, Schöneich C, Cohen RA. S-glutathiolation by peroxynitrite of p21ras at cysteine-118 mediates its direct activation and downstream signaling in endothelial cells. FASEB J 2006, 20: 518–20.

    CAS  PubMed  Google Scholar 

  11. Levrand S, Pesse B, Feihl F, et al. Peroxynitrite is a potent inhibitor of NF-kappaB activation triggered by inflammatory stimuli in cardiac and endothelial cell lines. J Biol Chem 2005, 280: 34878–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Platt DH, Bartoli M, El-Remessy AB, et al. Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3. Free Radic Biol Med 2005, 39: 1353–61.

    Article  CAS  PubMed  Google Scholar 

  13. Amiri F, Shaw S, Wang X, et al. Angiotensin II activation of the JAK/STAT pathway in mesangial cells is altered by high glucose. Kidney Int 2002, 61: 1605–16.

    Article  CAS  PubMed  Google Scholar 

  14. Banes AK, Shaw S, Jenkins J, et al. Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli. Am J Physiol Renal Physiol 2004, 286: F653–9.

    Article  CAS  PubMed  Google Scholar 

  15. El-Remessy AB, Behzadian MA, Abou-Mohamed G, Franklin T, Caldwell RW, Caldwell RB. Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor. Am J Pathol 2003, 162: 1995–2004.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Kang SW, Adler SG, Nast CC, et al. 12-lipoxygenase is increased in glucose-stimulated mesangial cells and in experimental diabetic nephropathy. Kidney Int 2001, 59: 1354–62.

    Article  CAS  PubMed  Google Scholar 

  17. Williams KJ, Qiu G, Usui HK, et al. Decorin deficiency enhances progressive nephropathy in diabetic mice. Am J Pathol 2007, 171: 1441–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Wolf G. Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway. Kidney Int 2006, 70: 1914–9.

    CAS  PubMed  Google Scholar 

  19. Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res 2004, 53: 131–42.

    CAS  PubMed  Google Scholar 

  20. Hamada Y, Miyata S, Nii-Kono T, et al. Overexpression of thioredoxin1 in transgenic mice suppresses development of diabetic nephropathy. Nephrol Dial Transplant 2007, 22: 1547–57.

    Article  CAS  PubMed  Google Scholar 

  21. Ogawa S, Mori T, Nako K, Ito S. Combination therapy with renin-angiotensin system inhibitors and the calcium channel blocker azelnidipine decreases plasma inflammatory markers and urinary oxidative stress markers in patients with diabetic nephropathy. Hypertens Res 2008, 31: 1147–55.

    Article  CAS  PubMed  Google Scholar 

  22. Ren XY, Li YN, Qi JS, Niu T. Peroxynitrite-induced protein nitration contributes to liver mitochondrial damage in diabetic rats. J Diabetes Complications 2008, 22: 357–64.

    Article  PubMed  Google Scholar 

  23. Qi JS, Li YN, Zhang BS, Niu T, Liang JH. Peroxynitrite mediates high glucose-induced osteoblast apoptosis. J Endocrinol Invest 2008, 31: 314–20.

    Article  CAS  PubMed  Google Scholar 

  24. Rösen P, Nawroth PP, King G, Möller W, Tritschler HJ, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev 2001, 17: 189–212.

    Article  PubMed  Google Scholar 

  25. Pryor WA, Squadrito GL. The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol 1995, 268: L699–722.

    CAS  PubMed  Google Scholar 

  26. Kamat JP. Peroxynitrite: a potent oxidizing and nitrating agent. Indian J Exp Biol 2006, 44: 436–47.

    CAS  PubMed  Google Scholar 

  27. El-Remessy AB, Al-Shabrawey M, Platt DH, et al. Peroxynitrite mediates VEGF’s angiogenic signal and function via a nitration-independent mechanism in endothelial cells. FASEB J 2007, 21: 2528–39.

    Article  CAS  PubMed  Google Scholar 

  28. Scott GS, Hooper DC. The role of uric acid in protection against peroxynitrite-mediated pathology. Med Hypotheses 2001, 56: 95–100.

    Article  CAS  PubMed  Google Scholar 

  29. Hooper DC, Spitsin S, Kean RB et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci U S A 1998, 95: 675–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Kooy NW, Royall JA, Ischiropoulos H, Beckman JS. Peroxynitrite-mediated oxidation of dihydrorhodamine 123. Free Radic Biol Med 1994, 16: 149–56.

    Article  CAS  PubMed  Google Scholar 

  31. Robinson KM, Morré JT, Beckman JS. Triuret: a novel product of peroxynitrite-mediated oxidation of urate. Arch Biochem Biophys 2004, 423: 213–7.

    Article  CAS  PubMed  Google Scholar 

  32. Freeman B. Free radical chemistry of nitric oxide. Looking at the dark side. Chest 1994, 105: 79S–84S.

    Article  CAS  PubMed  Google Scholar 

  33. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007, 87: 315–424.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Szabó C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 2007, 6: 662–80.

    Article  PubMed  Google Scholar 

  35. Thuraisingham RC, Nott CA, Dodd SM, Yaqoob MM. Increased nitrotyrosine staini ng in kidn eys from patients with diabetic nephropathy. Kidney Int 2000, 57: 1968–72.

    Article  CAS  PubMed  Google Scholar 

  36. Zhu B, Shen H, Zhou J, Lin F, Hu Y. Effects of simvastatin on oxidative stress in streptozotocin-induced diabetic rats: a role for glomeruli protection. Nephron Exp Nephrol 2005, 101: e1–8.

    Article  CAS  PubMed  Google Scholar 

  37. Marrero MB, Banes-Berceli AK, Stern DM, Eaton DC. Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am J Physiol Renal Physiol 2006, 290: F762–8.

    Article  CAS  PubMed  Google Scholar 

  38. Bryk R, Griffin P, Nathan C. Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 2000, 407: 211–5.

    Article  CAS  PubMed  Google Scholar 

  39. Lancel S, Tissier S, Mordon S, et al. Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats. J Am Coll Cardiol 2004, 43: 2348–58.

    Article  CAS  PubMed  Google Scholar 

  40. Parnham M, Sies H. Ebselen: prospective therapy for cerebral ischaemia. Expert Opin Investig Drugs 2000, 9: 607–19.

    Article  CAS  PubMed  Google Scholar 

  41. Fernandes DC, Medinas DB, Alves MJ, Augusto O. Tempol diverts peroxynitrite/carbon dioxide reactivity toward albumin and cells from protein-tyrosine nitration to protein-cysteine nitrosation. Free Radic Biol Med 2005, 38: 189–200.

    Article  CAS  PubMed  Google Scholar 

  42. Szabó C, Mabley JG, Moeller SM, et al. Part I: pathogenetic role of peroxynitrite in the development of diabetes and diabetic vascular complications: studies with FP15, a novel potent peroxynitrite decomposition catalyst. Mol Med 2002, 8: 571–80.

    PubMed Central  PubMed  Google Scholar 

  43. Bartesaghi S, Trujillo M, Denicola A, Folkes L, Wardman P, Radi R. Reactions of desferrioxamine with peroxynitrite-derived carbonate and nitrogen dioxide radicals. Free Radic Biol Med 2004, 36: 471–83.

    Article  CAS  PubMed  Google Scholar 

  44. Reiter CD, Teng RJ, Beckman JS. Superoxide reacts with nitric oxide to nitrate tyrosine at physiological pH via peroxynitrite. J Biol Chem 2000, 275: 32460–6.

    Article  CAS  PubMed  Google Scholar 

  45. Scott GS, Cuzzocrea S, Genovese T, Koprowski H, Hooper DC. Uric acid protects against secondary damage after spinal cord injury. Proc Natl Acad Sci USA 2005, 102: 3483–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Constantinescu CS, Freitag P, Kappos L. Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis. Mult Scler 2000, 6: 378–81.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Hebei Medical University, Shijiazhuang, China

    H. Wang, S. Liu, Q. Liu, Y. Shi & H. Duan MD

  2. Department of Biochemistry, Hebei Medical University, Shijiazhuang, China

    Y. Li

  3. Third Hospital, Hebei Medical University, Shijiazhuang, China

    H. Liu & X. M. Wang

Authors
  1. H. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Q. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X. M. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y. Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Duan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Duan MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, H., Li, Y., Liu, H. et al. Peroxynitrite mediates glomerular lesion of diabetic rat via JAK/STAT signaling pathway. J Endocrinol Invest 32, 844–851 (2009). https://doi.org/10.1007/BF03345756

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345756

Keywords

Search

Navigation