Advertisement

Curcumin Rescues Diabetic Renal Fibrosis by Targeting Superoxide-Mediated Wnt-Signaling Pathways

  • Cheng Ho
    Affiliations
    Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi, Taiwan
    Search for articles by this author
  • Yung-Chien Hsu
    Affiliations
    Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan

    Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan
    Search for articles by this author
  • Chen-Chou Lei
    Affiliations
    Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan

    Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan
    Search for articles by this author
  • Shu-Ching Mau
    Affiliations
    Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan

    Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan
    Search for articles by this author
  • Ya-Hsueh Shih
    Affiliations
    Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan

    Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan
    Search for articles by this author
  • Chun-Liang Lin
    Correspondence
    Correspondence: Chun-Liang Lin, MD, PhD, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, (613) 6 West, Chia-Pu Road, Pu-tzu City, Chiayi, Taiwan.
    Affiliations
    Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan

    Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan

    School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
    Search for articles by this author

      Abstract

      The purposes of this study were to investigate whether curcumin can weaken diabetic nephropathy by modulating both oxidative stress and renal injury from Wnt-signaling mediation. Wnt 5a/β-catenin depression and induction of superoxide synthesis are associated with high glucose (HG)–induced transforming growth factor beta 1 (TGF-β1) and fibronectin expression in mesangial cells. Curcumin resumes HG depression of Wnt/β-catenin signaling and alleviates HG induction of superoxide, TGF-β1 and fibronectin expression in renal mesangial cell. Exogenous curcumin alleviated urinary total proteinuria and serum superoxide level in diabetic rats. Based on laser-captured microdissection for quantitative real-time polymerase chain reaction, it was found that diabetes significantly increased TGF-β1, and fibronectin expression in line with depressed Wnt5a expression. Curcumin treatment reduced the TGF-β1, and fibronectin activation and the inhibiting effect of diabetes on Wnt5a/β-catenin expression in renal glomeruli. Immunohistochemistry showed that curcumin treatment significantly reduced 8-hydroxy-2′-deoxyguanosine, TGF-β1 and fibronectin, and was in line with the restoration of the suppressed Wnt5a expression immunoreactivities in glomeruli of diabetic rats. Curcumin alleviated extracellular matrix accumulation in diabetic nephropathy by not only preventing the diabetes-mediated superoxide synthesis but also resuming downregulation of Wnt/β-catenin signaling. These findings suggest that regulation of Wnt activity by curcumin is a feasible alternative strategy to rescue diabetic renal injury.

      Key Indexing Terms

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of the Medical Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Steffes M.W.
        • Osterby R.
        • Chavers B.
        • et al.
        Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients.
        Diabetes. 1989; 38: 1077-1081
        • Suzuki A.
        • Pelikan R.C.
        • Iwata J.
        WNT/β-catenin signaling regulates multiple steps of myogenesis by regulating step-specific targets.
        Mol Cell Biol. 2015; 35: 1763-1776
        • Ring A.
        • Kim Y.M.
        • Kahn M.
        Wnt/catenin signaling in adult stem cell physiology and disease.
        Stem Cell Rev. 2014; 10: 512-525
        • Lin C.L.
        • Wang J.Y.
        • Ko J.Y.
        • et al.
        Superoxide destabilization of beta-catenin augments apoptosis of high-glucose-stressed mesangial cells.
        Endocrinology. 2008; 149: 2934-2942
        • Lin C.L.
        • Wang J.Y.
        • Huang Y.T.
        • et al.
        Wnt/beta-catenin signaling modulates survival of high glucose-stressed mesangial cells.
        J Am Soc Nephrol. 2006; 17: 2812-2820
        • Lin C.L.
        • Cheng H.
        • Tung C.W.
        • et al.
        Simvastatin reverses high glucose-induced apoptosis of mesangial cells via modulation of Wnt signaling pathway.
        Am J Nephrol. 2008; 28: 290-297
        • Lin C.L.
        • Wang J.Y.
        • Ko J.Y.
        • et al.
        Dickkopf-1 promotes hyperglycemia-induced accumulation of mesangial matrix and renal dysfunction.
        J Am Soc Nephrol. 2010; 21: 124-135
        • Ho C.
        • Lee P.H.
        • Hsu Y.C.
        • et al.
        Sustained Wnt/β-catenin signaling rescues high glucose induction of transforming growth factor-β1-mediated renal fibrosis.
        Am J Med Sci. 2012; 344: 374-382
        • Gupta S.C.
        • Prasad S.
        • Kim J.H.
        • et al.
        Multitargeting by curcumin as revealed by molecular interaction studies.
        Nat Prod Rep. 2011; 28: 1937-1955
        • Zhou H.
        • Beevers C.S.
        • Huang S.
        The targets of curcumin.
        Curr Drug Targets. 2011; 12: 332-347
        • Chainani-Wu N.
        Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa).
        J Altern Complement Med. 2003; 9: 161-168
        • Nishiyama T.
        • Mae T.
        • Kishida H.
        • et al.
        Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice.
        J Agric Food Chem. 2005; 53: 959-963
        • Strimpakos A.S.
        • Sharma R.A.
        Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials.
        Antioxid Redox Signal. 2008; 10: 511-545
        • Sharma S.
        • Kulkarni S.K.
        • Chopra K.
        Curcumin the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats.
        Clin Exp Pharmacol Physiol. 2006; 33: 940-945
        • Tikoo K.
        • Meena R.L.
        • Kabra D.G.
        • et al.
        Change in post-translational modifications of histone H3, heat-shock protein-27 and MAP kinase p38 expression by curcumin in streptozotocin-induced type I diabetic nephropathy.
        Br J Pharmacol. 2008; 153: 1225-1231
        • Lin C.L.
        • Wang F.S.
        • Kuo Y.R.
        • et al.
        Ras modulation of superoxide activates ERK-dependent fibronectin expression in diabetes-induced renal injuries.
        Kidney Int. 2006; 69: 1593-1600
        • Hsu Y.C.
        • Lee P.H.
        • Lei C.C.
        • et al.
        Nitric oxide donors rescue diabetic nephropathy through oxidative-stress-and nitrosative-stress-mediated Wnt signaling pathways.
        J Diabetes Investig. 2015; 6: 24-34
        • Rossi L.
        • Mazzitelli S.
        • Arciello M.
        • et al.
        Benefits from dietary polyphenols for brain aging and Alzheimer’s disease.
        Neurochem Res. 2008; 33: 2390-2400
        • Aggarwal B.B.
        • Sundaram C.
        • Malani N.
        • et al.
        Curcumin: the Indian solid gold.
        Adv Exp Med Biol. 2007; 595: 1-75
        • Su C.C.
        • Lin J.G.
        • Li T.M.
        • et al.
        Curcumin-induced apoptosis of human colon cancer colo 205 cells through the production of ROS, Ca2+ and the activation of caspase-3.
        Anticancer Res. 2006; 26: 4379-4389
        • Vargas J.Y.
        • Ahumada J.
        • Arrázola M.S.
        • et al.
        WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers.
        Exp Neurol. 2015; 264: 14-25
        • Ahn J.
        • Lee H.
        • Kim S.
        • et al.
        Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling.
        Am J Physiol Cell Physiol. 2010; 298: C1510-C1516
        • Zhang X.
        • Yin W.K.
        • Shi X.D.
        • et al.
        Curcumin activates Wnt/β-catenin signaling pathway through inhibiting the activity of GSK-3β in APPs we transfected SY5Y cells.
        Eur J Pharm Sci. 2011; 42: 540-546
        • Prasad C.P.
        • Rath G.
        • Mathur S.
        • et al.
        Potent growth suppressive activity of curcumin in human breast cancer cells: modulation of Wnt/beta-catenin signaling.
        Chem Biol Interact. 2009; 181: 263-271
        • Zhang X.
        • Yin W.K.
        • Shi X.D.
        • et al.
        Curcumin activates Wnt/β-catenin signaling pathway through inhibiting the activity of GSK-3β in APPswe transfected SY5Y cells.
        Eur J Pharm Sci. 2011; 42: 540-546