Alpha-lipoic acid could attenuate the effect of chemerin-induced diabetic nephropathy progression

Document Type : Original Article

Authors

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, China

Abstract

Objective(s): Chemerin is associated with insulin resistance, obesity, and metabolic syndrome. α-lipoic acid (α-LA) is a potent antioxidant involved in the reduction of diabetic symptoms. This study aimed to investigate the relationship between chemerin and P38 MAPK in the progression of diabetic nephropathy (DN) and examine the effects of α-LA on chemerin-treated human mesangial cells (HMCs).
Materials and Methods: HMCs were transfected with a chemerin-overexpressing plasmid. HMCs were also treated with high-glucose, chemerin, α-LA, PDTC (pyrrolidine dithiocarbamate ammonium, NF-κB p65 inhibitor), and/or SB203580 (P38 MAPK inhibitor). Cell proliferation was tested using the Cell Counting Kit-8 assay. Collagen type IV and laminin were tested by ELISA. Chemerin expression was detected by qRT-PCR. The chemerin receptor was detected by immunohistochemistry. Interleukin-6 (IL-6), tumor necrosis factor-a (TNF-α), nuclear factor-κBp-p65 (NF-κB p-p65), transforming growth factor-β (TGF-β), and p-P38 mitogen-activated protein kinase (p-P38 MAPK) were evaluated by western blot.
Results: High-glucose culture increased the expression of the chemerin receptor. α-LA inhibited HMC proliferation. Chemerin overexpression increased collagen type IV and laminin expression. P38 MAPK signaling was activated by chemerin, resulting in up-regulation of IL-6, TNF-α, NF-κB p-p65, and TGF-β. SB203580, PDTC, and α-LA reversed the effects of chemerin, reducing IL-6, TNF-α, NF-κB p-p65, and TGF-β expression.
Conclusion: Chemerin might be involved in the occurrence and development of DN. α-LA might prevent the effects of chemerin on the progression of DN, possibly via the P38 MAPK pathway.

Keywords

References

1. Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy: A review. Int J Nephrol Renovasc Dis 2017;10:221-231
2. American Diabetes A. Standards of medical care in diabetes-2016 abridged for primary care providers. Clin Diabetes 2016;34:3-21.
3. Chamberlain JJ, Rhinehart AS, Shaefer CF, Jr, Neuman A. Diagnosis and management of diabetes: synopsis of the 2016 american diabetes association standards of medical care in diabetes. Ann Intern Med 2016;164:542-552.
4. Bakris GL. Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc 2011;86:444-56.
5.    Ma J, Sun F, Wang J, Jiang H, Lu J, Wang X, et al. Effects of aldosterone on chemerin expression and secretion in 3t3-l1 adipocytes. Exp Clin Endocrinol Diabetes 2018;126:187-193.
6.    Weng C, Shen Z, Li X, Jiang W, Peng L, Yuan H, et al. Effects of chemerin/CMKLR1 in obesity-induced hypertension and potential mechanism. Am J Transl Res 2017;9:3096-3104.
7.    Zylla S, Rettig R, Völzke H, Endlich K, Nauck M, Friedrich N. Serum chemerin levels are inversely associated with renal function in a general population. Clin Endocrinol (Oxf). 2018;88:146-153.
8.    Namazi N, Larijani B, Azadbakht L. Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials. Clin Nutr 2018;37:419-428.
9.    Saleh HM, El-Sayed YS, Naser SM, Eltahawy AS, Onoda A, Umezawa M. Efficacy of α-lipoic acid against cadmium toxicity on metal ion and oxidative imbalance, and expression of metallothionein and anti-oxidant genes in rabbit brain. Environ Sci Pollut Res Int 2017;24:24593-25601.
10.    Zhang J, McCullough PA. Lipoic acid in the prevention of acute kidney injury. Nephron 2016;134:133-140.
11.    Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 2014;6:80-120.
12.    Dong K, Hao P, Xu S, Liu S, Zhou W, Yue X, et al. Alpha-lipoic acid alleviates high-glucose suppressed osteogenic differentiation of MC3T3-E1 cells via anti-oxidant effect and pi3k/akt signaling pathway. Cell Physiol Biochem 2017;42:1897-1906.
13.    Sun Y, Yang P-P, Song Z-Y, Feng Y, Hu D-M, Hu J, et al. α-lipoic acid suppresses neuronal excitability and attenuates colonic hypersensitivity to colorectal distention in diabetic rats. J Pain Res 2017;10:1645-1655.
14.    Jurisic-Erzen D, Starcevic-Klasan G, Ivanac D, Peharec S, Girotto D, Jerkovic R. The effects of alpha-lipoic acid on diabetic myopathy. J Endocrinol Invest 2018;41:203-209.
15.    Adhikary L, Chow F, Nikolic-Paterson DJ, Stambe C, Dowling J, Atkins RC, et al. Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia 2004;47:1210-1222.
16.    Pang Y, Zhu H, Xu J, Yang L, Liu L, Li J. β-arrestin-2 is involved in irisin induced glucose metabolism in type 2 diabetes via p38 MAPK signaling. Exp Cell Res 2017;360:199-204.
17.    Dhanya R, Arya AD, Nisha P, Jayamurthy P. Quercetin, a lead compound against type 2 diabetes ameliorates glucose uptake via ampk pathway in skeletal muscle cell line. Front Pharmacol 2017;8:336-51.
18.    Guo S, Meng X-W, Yang X-S, Liu X-F, Ou-Yang C-H, Liu C. Curcumin administration suppresses collagen synthesis in the hearts of rats with experimental diabetes. Acta Pharmacol Sin 2018;39:195-204.
19.    Yeda X, Shaoqing L, Yayi H, Bo Z, Huaxin W, Hong C, et al. Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the P38-MAPK/TXNIP signaling activation in streptozotocin induced diabetic rats. Acta Cir Bras 2017;32:429-439.
20.    Zhang X, Wang L, Shang J, Ning LN, Zhao J, Dou Y, et al. Chemerin/ChemR23 promotes high glucose-induced IL-6 and TNF-α expressions in glomerular endothelial cells via p38 MAPK. Chinese Journal of Nephrology 2017;33:524-530.
21.    Shang J, Wang L, Zhang Y, Zhang S, Ning L, Zhao J, et al. Chemerin/ChemR23 axis promotes inflammation of glomerular endothelial cells in diabetic nephropathy. J Cell Mol Med. 2019;23:3417-3428.
22.    El Dayem SM, Battah AA, El Bohy Ael M, El Shehaby A, El Ghaffar EA. Relationship of plasma level of chemerin and vaspin to early atherosclerotic changes and cardiac autonomic neuropathy in adolescent type 1 diabetic patients. J Pediatr Endocrinol Metab 2015;28:265-273.
23.    Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, et al. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 2007;148:4687-4694.
24.    Gu P, Wang W, Yao Y, Xu Y, Wang L, Zang P, et al. Increased circulating chemerin in relation to chronic microvascular complications in patients with type 2 diabetes. Int J Endocrinol 2019;2019:8693516.
25.    Hu W, Feng P. Elevated serum chemerin concentrations are associated with renal dysfunction in type 2 diabetic patients. Diabetes Res Clin Pract 2011;91:159-163.
26.    Hu W, Yu Q, Zhang J, Liu D. Rosiglitazone ameliorates diabetic nephropathy by reducing the expression of Chemerin and ChemR23 in the kidney of streptozotocin-induced diabetic rats. Inflammation 2012;35:1287-1293.
27.    Salama FE, Anass QA, Abdelrahman AA, Saeed EB. Chemerin: A biomarker for cardiovascular disease in diabetic chronic kidney disease patients. Saudi J Kidney Dis Transpl 2016;27:977-984.
28.    Bartkoski S, Day M. Alpha-lipoic acid for treatment of diabetic peripheral neuropathy. Am Fam Physician 2016;93:786.
29.    Wang X, Lin H, Xu S, Jin Y, Zhang R. Alpha lipoic acid combined with epalrestat: A therapeutic option for patients with diabetic peripheral neuropathy. Drug Des Devel Ther 2018;12:2827-2840.
30.    Rochette L, Ghibu S, Muresan A, Vergely C. Alpha-lipoic acid: Molecular mechanisms and therapeutic potential in diabetes. Can J Physiol Pharmacol 2015;93:1021-1027.
31.    Han Y, Wang M, Shen J, Zhang Z, Zhao M, Huang J, et al. Differential efficacy of methylcobalamin and alpha-lipoic acid treatment on symptoms of diabetic peripheral neuropathy. Minerva Endocrinol 2018;43:11-18.
32.    Papanas N, Ziegler D. Efficacy of alpha-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother 2014;15:2721-2731.
33.    Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 2009;1790:1149-1160.
34.    Sadeghiyan Galeshkalami N, Abdollahi M, Najafi R, Baeeri M, Jamshidzade A, Falak R, et al. Alpha-lipoic acid and coenzyme Q10 combination ameliorates experimental diabetic neuropathy by modulating oxidative stress and apoptosis. Life Sci 2019;216:101-110.
35.    Chukanova EI, Chukanova AS. [Alpha-lipoic acid in the treatment of diabetic polyneuropathy]. Zh Nevrol Psikhiatr Im S S Korsakova 2018;118:103-109.
36.    Agathos E, Tentolouris A, Eleftheriadou I, Katsaouni P, Nemtzas I, Petrou A, et al. Effect of alpha-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J Int Med Res 2018;46:1779-1790.
37.    Cakici N, Fakkel TM, van Neck JW, Verhagen AP, Coert JH. Systematic review of treatments for diabetic peripheral neuropathy. Diabet Med 2016;33:1466-1476.
38.    Varkonyi T, Korei A, Putz Z, Martos T, Keresztes K, Lengyel C, et al. Advances in the management of diabetic neuropathy. Minerva Med 2017;108:419-437.
39.    Salehi B, Berkay Yilmaz Y, Antika G, Boyunegmez Tumer T, Fawzi Mahomoodally M, Lobine D, et al. Insights on the Use of alpha-Lipoic Acid for Therapeutic Purposes. Biomolecules 2019;9:356.
40.    Ibrahimpasic K. Alpha lipoic acid and glycaemic control in diabetic neuropathies at type 2 diabetes treatment. Med Arch 2013;67:7-9.
41.    Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 2014;6:80-120.
42.    Nguyen N, Takemoto JK. a case for alpha-lipoic acid as an alternative treatment for diabetic polyneuropathy. J Pharm Pharm Sci 2018;21:177s-191s.
43.    Snyder MJ, Gibbs LM, Lindsay TJ. Treating painful diabetic peripheral neuropathy: an update. Am Fam Physician. 2016;94:227-234.
44.    Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic acid and diabetic neuropathy. Rev Diabet Stud 2009;6:230-236.
45.    Seyit DA, Degirmenci E, Oguzhanoglu A. Evaluation of electrophysiological effects of melatonin and alpha lipoic acid in rats with streptozotocine induced diabetic neuropathy. Exp Clin Endocrinol Diabetes 2016;124:300-306.
46.    Won JC, Kwon HS, Moon SS, Chun SW, Kim CH, Park IB, et al. Gamma-linolenic acid versus alpha-lipoic acid for treating painful diabetic neuropathy in adults: A 12-week, double-placebo, randomized, noninferiority trial. Diabetes Metab J 2020;44:542-54.
47.    Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, et al. Efficacy and safety of anti-oxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care 2011;34:2054-2060.
48.    Feng B, Yan XF, Xue JL, Xu L, Wang H. The protective effects of alpha-lipoic acid on kidneys in type 2 diabetic Goto-Kakisaki rats via reducing oxidative stress. Int J Mol Sci 2013;14:6746-6756.
49.    Yi X, Xu L, Hiller S, Kim HS, Nickeleit V, James LR, et al. Reduced expression of lipoic acid synthase accelerates diabetic nephropathy. J Am Soc Nephrol 2012;23:103-111.
50.    Xu L, Hiller S, Simington S, Nickeleit V, Maeda N, James LR, et al. Influence of different levels of lipoic acid synthase gene expression on diabetic nephropathy. PLoS One 2016;11:e0163208.
51.    Zabel BA, Silverio AM, Butcher EC. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J Immunol 2005;174:244-251.
52.    Hu W, Feng P. Elevated serum chemerin concentrations are associated with renal dysfunction in type 2 diabetic patients. Diabetes Res Clin Pract 2011;91:159-163.
53.    Hu W, Yu Q, Zhang J, Liu D. Rosiglitazone ameliorates diabetic nephropathy by reducing the expression of Chemerin and ChemR23 in the kidney of streptozotocin-induced diabetic rats. Inflammation 2012;35:1287-1293.
54.    Wang Y, Liu L, Peng W, Liu H, Liang L, Zhang X, et al. Ski-related novel protein suppresses the development of diabetic nephropathy by modulating transforming growth factor-beta signaling and microRNA-21 expression. J Cell Physiol 2019;234:17925-17936.
55.    Ding H, Xu Y, Jiang N. Upregulation of miR-101a suppresses chronic renal fibrosis by regulating KDM3A via blockade of the YAP-TGF-beta-smad signaling pathway. Mol Ther Nucleic Acids 2020;19:1276-1289.
56.    He X, Cheng R, Huang C, Takahashi Y, Yang Y, Benyajati S, et al. A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-beta/Smad signaling. Signal Transduct Target Ther 2020;5:45-63.
57.    Komers R, Lindsley JN, Oyama TT, Cohen DM, Anderson S. Renal p38 MAP kinase activity in experimental diabetes. Lab Invest 2007;87:548-558.
58.    Kang SW, Adler SG, Lapage J, Natarajan R. p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli. Kidney Int 2001;60:543-552.
59.    Kim SI, Kwak JH, Zachariah M, He Y, Wang L, Choi ME. TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. Am J Physiol Renal Physiol 2007;292:F1471-F1478.
60.    Hills CE, Squires PE. TGF-beta1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol 2010;31:68-74.
61.    Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, et al. Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 2001;50:1495-1504.
62.    Kaneko K, Miyabe Y, Takayasu A, Fukuda S, Miyabe C, Ebisawa M, et al. Chemerin activates fibroblast-like synoviocytes in patients with rheumatoid arthritis. Arthritis Res Ther 2011;13:R158.
63.    Sell H, Laurencikiene J, Taube A, Eckardt K, Cramer A, Horrighs A, et al. Chemerin is a novel adipocyte-derived factor inducing insulin resistance in primary human skeletal muscle cells. Diabetes 2009;58:2731-2740.
64.    Kaur J, Adya R, Tan BK, Chen J, Randeva HS. Identification of chemerin receptor (ChemR23) in human endothelial cells: Chemerin-induced endothelial angiogenesis. Biochem Biophys Res Commun 2010;391:1762-1768.
65.    Yi X, Xu L, Hiller S, Kim H-S, Nickeleit V, James LR, et al. Reduced expression of lipoic acid synthase accelerates diabetic nephropathy. J Am Soc Nephrol 2012;23:103-111.
66.    Feng B, Yan X-F, Xue J-L, Xu L, Wang H. The protective effects of α-lipoic acid on kidneys in type 2 diabetic Goto-Kakisaki rats via reducing oxidative stress. Int J Mol Sci 2013;14:6746-6756.
67.    Yi X, Nickeleit V, James LR, Maeda N. α-Lipoic acid protects diabetic apolipoprotein E-deficient mice from nephropathy. J Diabetes Complications 2011;25:193-201.
68.    Lee SJ, Kang JG, Ryu OH, Kim CS, Ihm S-H, Choi MG, et al. Effects of alpha-lipoic acid on transforming growth factor beta1-p38 mitogen-activated protein kinase-fibronectin pathway in diabetic nephropathy. Metabolism. 2009;58:616-623.
69.    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883-899.
70.    Kim J, Bhattacharjee R, Dayyat E, Snow AB, Kheirandish-Gozal L, Goldman JL, et al. Increased cellular proliferation and inflammatory cytokines in tonsils derived from children with obstructive sleep apnea. Pediatr Res 2009;66:423-428.
71.    Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2018;9:7204-7218.
72.    Moens U, Kostenko S, Sveinbjornsson B. The role of mitogen-activated protein kinase-activated protein kinases (mapkapks) in inflammation. Genes 2013;4:101-133.
73.    Lu N, Malemud CJ. Extracellular signal-regulated kinase: A regulator of cell growth, inflammation, chondrocyte and bone cell receptor-mediated gene expression. Int J Mol Sci 2019;20:3792-3823.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 8
August 2021
Pages 1107-1116

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