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Diabetologia
Erschienen in: Diabetologia 7/2016

26.04.2016 | Article

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

verfasst von: Hao Wu, Lili Kong, Yi Tan, Paul N. Epstein, Jun Zeng, Junlian Gu, Guang Liang, Maiying Kong, Xiangmei Chen, Lining Miao, Lu Cai

Erschienen in: Diabetologia | Ausgabe 7/2016

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Abstract

Aims/hypothesis

Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy.

Methods

Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]).

Results

Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis.

Conclusions/interpretation

The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21.
Literatur
1.
Dronavalli S, Duka I, Bakris GL (2008) The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab 4:444–452CrossRefPubMed
2.
Zheng H, Whitman SA, Wu W et al (2011) Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60:3055–3066CrossRefPubMedPubMedCentral
3.
Miyata T, Suzuki N, van Ypersele de Strihou C (2013) Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology? Kidney Int 84:693–702CrossRefPubMed
4.
Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD (2010) The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59:850–860CrossRefPubMedPubMedCentral
5.
Nguyen T, Sherratt PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43:233–260CrossRefPubMed
6.
Kang ES, Woo IS, Kim HJ et al (2007) Up-regulation of aldose reductase expression mediated by phosphatidylinositol 3-kinase/Akt and Nrf2 is involved in the protective effect of curcumin against oxidative damage. Free Radic Biol Med 43:535–545CrossRefPubMed
7.
Huang J, Huang K, Lan T et al (2013) Curcumin ameliorates diabetic nephropathy by inhibiting the activation of the SphK1-S1P signaling pathway. Mol Cell Endocrinol 365:231–240CrossRefPubMed
8.
Soetikno V, Sari FR, Lakshmanan AP et al (2013) Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keap1 pathway. Mol Nutr Food Res 57:1649–1659CrossRefPubMed
9.
Li D, Lu Z, Jia J, Zheng Z, Lin S (2013) Curcumin ameliorates Podocytic adhesive capacity damage under mechanical stress by inhibiting miR-124 expression. Kidney Blood Press Res 38:61–71CrossRefPubMed
10.
Soetikno V, Watanabe K, Sari FR et al (2011) Curcumin attenuates diabetic nephropathy by inhibiting PKC-α and PKC-β1 activity in streptozotocin-induced type I diabetic rats. Mol Nutr Food Res 55:1655–1665CrossRefPubMed
11.
Tikoo K, Meena RL, Kabra DG, Gaikwad AB (2008) 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 153:1225–1231CrossRefPubMedPubMedCentral
12.
Pan Y, Wang Y, Zhao Y et al (2014) Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy. Diabetes 63:3497–3511CrossRefPubMed
13.
Pan Y, Zhang X, Wang Y et al (2013) Targeting JNK by a new curcumin analog to inhibit NF-kB-mediated expression of cell adhesion molecules attenuates renal macrophage infiltration and injury in diabetic mice. PLoS One 8:e79084CrossRefPubMedPubMedCentral
14.
Liu Y, Wang Y, Miao X et al (2014) Inhibition of JNK by compound C66 prevents pathological changes of the aorta in STZ-induced diabetes. J Cell Mol Med 18:1203–1212CrossRefPubMedPubMedCentral
15.
Bhatt K, Mi QS, Dong Z (2011) microRNAs in kidneys: biogenesis, regulation, and pathophysiological roles. Am J Physiol Renal Physiol 300:F602–F610CrossRefPubMedPubMedCentral
16.
Eades G, Yang M, Yao Y, Zhang Y, Zhou Q (2011) miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem 286:40725–40733CrossRefPubMedPubMedCentral
17.
Wei J, Zhang Y, Luo Y et al (2013) Aldose reductase regulates miR-200a-3p/141-3p to coordinate Keap1-Nrf2, Tgfβ1/2, and Zeb1/2 signaling in renal mesangial cells and the renal cortex of diabetic mice. Free Radic Biol Med 67C:91–102
18.
Ali S, Ahmad A, Banerjee S et al (2010) Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res 70:3606–3617CrossRefPubMedPubMedCentral
19.
Soubani O, Ali AS, Logna F, Ali S, Philip PA, Sarkar FH (2012) Re-expression of miR-200 by novel approaches regulates the expression of PTEN and MT1-MMP in pancreatic cancer. Carcinogenesis 33:1563–1571CrossRefPubMedPubMedCentral
20.
Dey N, Das F, Mariappan MM et al (2011) MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes. J Biol Chem 286:25586–25603CrossRefPubMedPubMedCentral
21.
Wang JY, Gao YB, Zhang N et al (2014) miR-21 overexpression enhances TGF-β1-induced epithelial-to-mesenchymal transition by target smad7 and aggravates renal damage in diabetic nephropathy. Mol Cell Endocrinol 392:163–172CrossRefPubMed
22.
Zhong X, Chung AC, Chen HY et al (2013) miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia 56:663–674CrossRefPubMed
23.
Mudduluru G, George-William JN, Muppala S et al (2011) Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci Rep 31:185–197CrossRefPubMed
24.
Zhang Z, Chen J, Zhou S et al (2015) Magnolia bioactive constituent 4-O-methylhonokiol prevents the impairment of cardiac insulin signaling and the cardiac pathogenesis in high-fat diet-induced obese mice. Int J Biol Sci 11:879–891CrossRefPubMedPubMedCentral
25.
Cai L, Wang J, Li Y et al (2005) Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy. Diabetes 54:1829–1837CrossRefPubMed
26.
Wang Y, Feng W, Xue W et al (2009) Inactivation of GSK-3β by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes 58:1391–1402CrossRefPubMedPubMedCentral
27.
Wu H, Zhou S, Kong L et al (2014) Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice. Toxicol Lett 232:340–348CrossRefPubMed
28.
Erkens R, Kramer CM, Luckstadt W et al (2015) Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med 89:906–917CrossRefPubMed
29.
Nakao A, Okumura K, Ogawa H (2002) Smad7: a new key player in TGF-β-associated disease. Trends Mol Med 8:361–363CrossRefPubMed
30.
Wang JY, Gao YB, Zhang N et al (2014) Tongxinluo ameliorates renal structure and function by regulating miR-21-induced epithelial-to-mesenchymal transition in diabetic nephropathy. Am J Physiol Renal Physiol 306:F486–F495CrossRefPubMed
31.
Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283:1026–1033CrossRefPubMed
32.
Bitomsky N, Bohm M, Klempnauer KH (2004) Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun. Oncogene 23:7484–7493CrossRefPubMed
33.
Keshari KR, Wilson DM, Sai V et al (2014) Non-invasive in vivo imaging of diabetes-induced renal oxidative stress and response to therapy using hyperpolarized 13C dehydroascorbate magnetic resonance. Diabetes 64:344–352CrossRefPubMedPubMedCentral
34.
35.
Yagishita Y, Fukutomi T, Sugawara A et al (2014) Nrf2 protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice. Diabetes 63:605–618CrossRefPubMed
36.
Li B, Cui W, Tan Y et al (2014) Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition. J Cell Mol Med 18:895–906CrossRefPubMedPubMedCentral
37.
Balogun E, Hoque M, Gong P et al (2003) Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 371:887–895CrossRefPubMedPubMedCentral
38.
Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G (2012) Curcumin--from molecule to biological function. Angew Chem Int Ed Engl 51:5308–5332CrossRefPubMed
39.
Soetikno V, Suzuki K, Veeraveedu PT et al (2013) Molecular understanding of curcumin in diabetic nephropathy. Drug Discov Today 18:756–763CrossRefPubMed
40.
Teiten MH, Dicato M, Diederich M (2013) Curcumin as a regulator of epigenetic events. Mol Nutr Food Res 57:1619–1629CrossRefPubMed
41.
Chen HY, Huang XR, Wang W et al (2011) The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential. Diabetes 60:590–601CrossRefPubMedPubMedCentral
42.
Chung AC, Zhang H, Kong YZ et al (2010) Advanced glycation end-products induce tubular CTGF via TGF-β-independent Smad3 signaling. J Am Soc Nephrol 21:249–260CrossRefPubMedPubMedCentral
43.
Ai J, Nie J, He J et al (2014) GQ5 hinders renal fibrosis in obstructive nephropathy by selectively inhibiting TGF-β-induced Smad3 phosphorylation. J Am Soc Nephrol 26:1827–1838CrossRefPubMed
44.
Ishida T, Haneda M, Maeda S, Koya D, Kikkawa R (1999) Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen-activated protein kinase. Diabetes 48:595–602CrossRefPubMed
45.
Bennett BL, Sasaki DT, Murray BW et al (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 98:13681–13686CrossRefPubMedPubMedCentral
46.
Wahid F, Shehzad A, Khan T, Kim YY (2010) MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim Biophys Acta 1803:1231–1243CrossRefPubMed
47.
48.
Gold R, Kappos L, Arnold DL et al (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107CrossRefPubMed
49.
Ellison DH (2014) Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. N Engl J Med 370:1768PubMed
50.
Tan SM, Sharma A, Stefanovic N et al (2014) Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-associated atherosclerosis and improves diabetic kidney disease. Diabetes 63:3091–3103CrossRefPubMed
Metadaten
Titel
C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21
verfasst von
Hao Wu
Lili Kong
Yi Tan
Paul N. Epstein
Jun Zeng
Junlian Gu
Guang Liang
Maiying Kong
Xiangmei Chen
Lining Miao
Lu Cai
Publikationsdatum
26.04.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
Diabetologia / Ausgabe 7/2016
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-3958-8

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