Probucol modulates Nrf2 function and ameliorates diabetic nephropathy in db/db mice
Main Article Content
Abstract
Background: In this study, we hypothesized that probucol can ameliorate diabetic nephropathy by inducing Nuclear factor erythroid 2-related factor 2 (Nrf2). We examined and compared the effects of probucol and pitavastatin on diabetic nephropathy in db/db mice. Methods: Db/db mice were fed with normal chow with or without 0.1% probucol or 0.005% pitavastatin for eight weeks. Blood and urine samples were collected before administration and four and eight weeks after the treatment. We also performed a histological analysis at the end of the study. Results: Probucol, but not pitavastatin, treatment significantly decreased both serum cholesterol and triglycerides by more than 50%. Probucol and pitavastatin treatment decreased 24 hour urinary albumin excretion and glomerular Nrf2 expression and produced a histological improvement of diabetic nephropathy. Conclusions: Our data demonstrates that probucol can ameliorate diabetic nephropathy through its cholesterol-lowering effect and possibly its modifing effects on Nrf2 function in diabetes.
Article Details
How to Cite
ABE, Hideharu et al.
Probucol modulates Nrf2 function and ameliorates diabetic nephropathy in db/db mice.
Medical Research Archives, [S.l.], v. 4, n. 8, dec. 2016.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/935>. Date accessed: 26 dec. 2024.
Keywords
diabetic nephropathy; probucol; Nrf2
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med. 1994;330(1):15-8.
Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615–25
Carew TE, Schwenke DC, Steinberg D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci U S A. 1987;84(21):7725-9.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis. 2009;54(5):810-9.
Du Y, Zhang X, Ji H, Liu H, Li S, Li L. Probucol and atorvastatin in combination protect rat brains in MCAO model: upregulating Peroxiredoxin2, Foxo3a and Nrf2 expression. Neurosci Lett. 2012;509(2):110-5.
Endo K, Miyashita Y, Sasaki H, Ohira M, Saiki A, Koide N, et al. Probucol delays progression of diabetic nephropathy. Diabetes Res Clin Pract. 2006;71(2):156-63.
Endo K, Saiki A, Yamaguchi T, Sakuma K, Sasaki H, Ban N, et al. Probucol suppresses initiation of chronic hemodialysis therapy and renal dysfunction-related death in diabetic nephropathy patients: Sakura study. J Atheroscler Thromb. 2013;20(5):494-502.
Heiss EH1, Schachner D, Zimmermann K, Dirsch VM. eCollection Glucose availability is a decisive factor for Nrf2-mediated gene expression. Redox Biol. 2013;1:359-65.
Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes. 2010;59(4):850-60.
Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med. 2008;233(1):4-11.
Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47(9):1304-9.
Kedziora-Kornatowska KZ, Luciak M, Blaszczyk J, Pawlak W. Lipid peroxidation and activities of antioxidant enzymes in erythrocytes of patients with non-insulin dependent diabetes with or without diabetic nephropathy. Nephrol Dial Transplant. 1998;13(11):2829-32.
Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima A, et al. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1987;84(16):5928-31.
Kwan BC, Beddhu S, Kronenberg F, Cheung AK. Does statin therapy improve cardiovascular outcomes in patients with type 2 diabetes receiving hemodialysis? Nat Clin Pract Nephrol. 2006;2(2):76-7.
Matsubara T, Abe H, Arai H, Nagai K, Mima A, Kanamori H, et al. Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Lab Invest. 2006;86(4):357-68.
Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC. Structural-functional relationships in diabetic nephropathy. J Clin Invest. 1984;74(4):1143-55.
Moorhead JF, Chan MK, El-Nahas M, Varghese Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet. 1982;2(8311):1309-11.
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284(20):13291-5.
Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327-36.
Reusch JE. Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose? J Clin Invest. 2003;112:986–8
Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol. 2006;17(7):2006-16.
Serhan, C. N. A search for endogenous mechanisms of anti-inflammation uncovers novel chemical mediators: missing links to resolution. Histochem Cell Biol. 2004;122, 305-21.
Shahzad K, Bock F, Al-Dabet MM, Gadi I, Nazir S, Wang H, et al. Stabilization of endogenous Nrf2 by minocycline protects against Nlrp3-inflammasome induced diabetic nephropathy. Sci Rep. 2016;6:34228.
Tamura Y, Murayama T, Minami M, Matsubara T, Yokode M, Arai H. Ezetimibe ameliorates early diabetic nephropathy in db/db mice. J Atheroscler Thromb. 2012;19(7):608-18.
Tamura Y, Murayama T, Minami M, Yokode M, Arai H. Differential effect of statins on diabetic nephropathy in db/db mice. Int J Mol Med. 2011;28(5):683-7.
Yamabe S, Hirose J, Uehara Y, Okada T, Okamoto N, Oka K, et al. Intracellular accumulation of advanced glycation end products induces apoptosis via endoplasmic reticulum stress in chondrocytes. FEBS J. 2013;280(7):1617-29.
Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, et al. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest. 2001;108(2):261-8.
Zheng H1, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes. 2011;60(11):3055-66.
Zhou G, Wang Y, He P, Li D. Probucol inhibited Nox2 expression and attenuated podocyte injury in type 2 diabetic nephropathy of db/db mice. Biol Pharm Bull. 2013;36(12):1883-90.
Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med. 1994;330(1):15-8.
Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615–25
Carew TE, Schwenke DC, Steinberg D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci U S A. 1987;84(21):7725-9.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis. 2009;54(5):810-9.
Du Y, Zhang X, Ji H, Liu H, Li S, Li L. Probucol and atorvastatin in combination protect rat brains in MCAO model: upregulating Peroxiredoxin2, Foxo3a and Nrf2 expression. Neurosci Lett. 2012;509(2):110-5.
Endo K, Miyashita Y, Sasaki H, Ohira M, Saiki A, Koide N, et al. Probucol delays progression of diabetic nephropathy. Diabetes Res Clin Pract. 2006;71(2):156-63.
Endo K, Saiki A, Yamaguchi T, Sakuma K, Sasaki H, Ban N, et al. Probucol suppresses initiation of chronic hemodialysis therapy and renal dysfunction-related death in diabetic nephropathy patients: Sakura study. J Atheroscler Thromb. 2013;20(5):494-502.
Heiss EH1, Schachner D, Zimmermann K, Dirsch VM. eCollection Glucose availability is a decisive factor for Nrf2-mediated gene expression. Redox Biol. 2013;1:359-65.
Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes. 2010;59(4):850-60.
Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med. 2008;233(1):4-11.
Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47(9):1304-9.
Kedziora-Kornatowska KZ, Luciak M, Blaszczyk J, Pawlak W. Lipid peroxidation and activities of antioxidant enzymes in erythrocytes of patients with non-insulin dependent diabetes with or without diabetic nephropathy. Nephrol Dial Transplant. 1998;13(11):2829-32.
Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima A, et al. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1987;84(16):5928-31.
Kwan BC, Beddhu S, Kronenberg F, Cheung AK. Does statin therapy improve cardiovascular outcomes in patients with type 2 diabetes receiving hemodialysis? Nat Clin Pract Nephrol. 2006;2(2):76-7.
Matsubara T, Abe H, Arai H, Nagai K, Mima A, Kanamori H, et al. Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Lab Invest. 2006;86(4):357-68.
Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC. Structural-functional relationships in diabetic nephropathy. J Clin Invest. 1984;74(4):1143-55.
Moorhead JF, Chan MK, El-Nahas M, Varghese Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet. 1982;2(8311):1309-11.
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284(20):13291-5.
Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327-36.
Reusch JE. Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose? J Clin Invest. 2003;112:986–8
Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol. 2006;17(7):2006-16.
Serhan, C. N. A search for endogenous mechanisms of anti-inflammation uncovers novel chemical mediators: missing links to resolution. Histochem Cell Biol. 2004;122, 305-21.
Shahzad K, Bock F, Al-Dabet MM, Gadi I, Nazir S, Wang H, et al. Stabilization of endogenous Nrf2 by minocycline protects against Nlrp3-inflammasome induced diabetic nephropathy. Sci Rep. 2016;6:34228.
Tamura Y, Murayama T, Minami M, Matsubara T, Yokode M, Arai H. Ezetimibe ameliorates early diabetic nephropathy in db/db mice. J Atheroscler Thromb. 2012;19(7):608-18.
Tamura Y, Murayama T, Minami M, Yokode M, Arai H. Differential effect of statins on diabetic nephropathy in db/db mice. Int J Mol Med. 2011;28(5):683-7.
Yamabe S, Hirose J, Uehara Y, Okada T, Okamoto N, Oka K, et al. Intracellular accumulation of advanced glycation end products induces apoptosis via endoplasmic reticulum stress in chondrocytes. FEBS J. 2013;280(7):1617-29.
Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, et al. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest. 2001;108(2):261-8.
Zheng H1, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes. 2011;60(11):3055-66.
Zhou G, Wang Y, He P, Li D. Probucol inhibited Nox2 expression and attenuated podocyte injury in type 2 diabetic nephropathy of db/db mice. Biol Pharm Bull. 2013;36(12):1883-90.