CCR2 knockout ameliorates obesity-induced kidney injury through inhibiting oxidative stress and ER stress


Autoři: Seung Joo Lee aff001;  Jeong Suk Kang aff001;  Hong Min Kim aff003;  Eun Soo Lee aff003;  Ji-Hye Lee aff004;  Choon Hee Chung aff003;  Eun Young Lee aff001
Působiště autorů: Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea aff001;  Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Korea aff002;  Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea aff003;  Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea aff004
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222352

Souhrn

CCL2/CCR2 signaling is believed to play an important role in kidney diseases. Several studies have demonstrated that blocking of CCR2 has a therapeutic effect on kidney diseases. However, the effects of CCR2 knockout on obesity-induced kidney injury remain unclear. We investigated the therapeutic effects and the mechanism of CCL2/CCR2 signaling in obesity-induced kidney injury. We used C57BL/6-CCR2 wild type and C57BL/6-CCR2 knockout mice: Regular diet wild type (RD WT), RD CCR2 knockout (RD KO), High-fat diet WT (HFD WT), HFD CCR2 KO (HFD KO). Body weight of WT mice was significantly increased after HFD. However, the body weight of HFD KO mice was not decreased compared to HFD WT mice. Food intake and calorie showed no significant differences between HFD WT and HFD KO mice. Glucose, insulin, total cholesterol, and triglycerides levels increased in HFD WT mice were decreased in HFD KO mice. Insulin resistance, increased insulin secretion, and lipid accumulation showed in HFD WT mice were improved in HFD KO mice. Increased desmin expression, macrophage infiltration, and TNF-α in HFD mice were reduced in HFD KO mice. HFD-induced albuminuria, glomerular hypertrophy, glomerular basement membrane thickening, and podocyte effacement were restored by CCR2 depletion. HFD-induced elevated expressions of xBP1, Bip, and Nox4 at RNA and protein levels were significantly decreased in HFD KO. Therefore, blockade of CCL2/CCR2 signaling by CCR2 depletion might ameliorate obesity-induced albuminuria through blocking oxidative stress, ER stress, and lipid accumulation.

Klíčová slova:

Biology and life sciences – Ecology – Community ecology – Trophic interactions – Anatomy – Renal system – Kidneys – Physiology – Physiological parameters – Obesity – Biochemistry – Hormones – Cell biology – Cellular types – Animal cells – Blood cells – White blood cells – Macrophages – Immune cells – Ecology and environmental sciences – Medicine and health sciences – Body weight – Endocrinology – Diabetic endocrinology – Insulin – Endocrine physiology – Immunology – Research and analysis methods – Animal studies – Experimental organism systems – Model organisms – Mouse models – Animal models


Zdroje

1. Schmid PM, Heid I, Buechler C, Steege A, Resch M, Birner C, et al. Expression of fourteen novel obesity-related genes in Zucker diabetic fatty rats. Cardiovasc Diabetol. 2012;11:48. doi: 10.1186/1475-2840-11-48 22553958

2. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005;96(9):939–949. doi: 10.1161/01.RES.0000163635.62927.34 15890981

3. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114(2):147–152. doi: 10.1172/JCI22422 15254578

4. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111–1119. doi: 10.1172/JCI25102 15864338

5. Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, Hall JE. Obesity, hypertension, and chronic kidney disease. Int J Nephrol Renovasc Dis. 2014;7:75–88. doi: 10.2147/IJNRD.S39739 24600241

6. Ding W, Cheung WW, Mak RH. Impact of obesity on kidney function and blood pressure in children. World J Nephrol. 2015;4(2):223–229. doi: 10.5527/wjn.v4.i2.223 25949935

7. Weiss R, Kaufman FR. Metabolic complications of childhood obesity: identifying and mitigating the risk. Diabetes Care. 2008;31 Suppl 2:S310–316.

8. Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep. 2005;5(1):70–75. 15663921

9. Kim CS, Park HS, Kawada T, Kim JH, Lim D, Hubbard NE, et al. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond). 2006;30(9):1347–1355.

10. Herder C, Baumert J, Thorand B, Koenig W, de Jager W, Meisinger C, et al. Chemokines as risk factors for type 2 diabetes: results from the MONICA/KORA Augsburg study, 1984–2002. Diabetologia. 2006;49(5):921–929. doi: 10.1007/s00125-006-0190-y 16532324

11. Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology. 1992;130(1):43–52. doi: 10.1210/endo.130.1.1727716 1727716

12. Cheung AT, Ree D, Kolls JK, Fuselier J, Coy DH, Bryer-Ash M. An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha. Endocrinology. 1998;139(12):4928–4935. doi: 10.1210/endo.139.12.6336 9832430

13. Sell H, Eckel J. Monocyte chemotactic protein-1 and its role in insulin resistance. Curr Opin Lipidol. 2007;18(3):258–262. doi: 10.1097/MOL.0b013e3281338546 17495598

14. Sell H, Eckel J. Chemotactic cytokines, obesity and type 2 diabetes: in vivo and in vitro evidence for a possible causal correlation? Proc Nutr Soc. 2009;68(4):378–384. doi: 10.1017/S0029665109990218 19698204

15. Adams DH, Lloyd AR. Chemokines: leucocyte recruitment and activation cytokines. Lancet. 1997;349(9050):490–495. doi: 10.1016/s0140-6736(96)07524-1 9040590

16. Verzola D, Cappuccino L, D'Amato E, Villaggio B, Gianiorio F, Mij M, et al. Enhnaced glomerular Too-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int. 2014;86:1229–1243. doi: 10.1038/ki.2014.116 24786705

17. Aon MA, Bhatt N, Cortassa SC. Mitochondrial and cellular mechanisms for managing lipid excess. Front Physiol. 2014;5:282. doi: 10.3389/fphys.2014.00282 25132820

18. Schrauwen P, Schrauwen-Hinderling V, Hoeks J, Hesselink MK. Mitochondrial dysfunction and lipotoxicity. Biochim Biophys Acta. 2010;1801(3):266–271. doi: 10.1016/j.bbalip.2009.09.011 19782153

19. Li N, Yi FX, Spurrier JL, Bobrowitz CA, Zou AP. Production of superoxide through NADH oxidase in thick ascending limb of Henle's loop in rat kidney. Am J Physiol Renal Physiol. 2002;282(6):F1111–1119. doi: 10.1152/ajprenal.00218.2001 11997328

20. Zou AP, Li N, Cowley AW Jr., Production and actions of superoxide in the renal medulla. Hypertension. 2001;37(2 Pt 2):547–553.

21. Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P, et al. Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res. 2009;105(3):249–259. doi: 10.1161/CIRCRESAHA.109.193722 19574552

22. Orient A, Donko A, Szabo A, Leto TL, Geiszt M. Novel sources of reactive oxygen species in the human body. Nephrol Dial Transplant. 2007;22(5):1281–1288. doi: 10.1093/ndt/gfm077 17347280

23. Shiose A, Kuroda J, Tsuruya K, Hirai M, Hirakata H, Naito S, et al. A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem. 2001;276(2):1417–1423. doi: 10.1074/jbc.M007597200 11032835

24. Kolattukudy PE, Niu J. Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway. Circ Res. 2012;110(1):174–189. doi: 10.1161/CIRCRESAHA.111.243212 22223213

25. Segerer S, Cui Y, Eitner F, Goodpaster T, Hudkins KL, Mack M, et al. Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis. 2001;37(3):518–531. 11228176

26. Wada T, Yokoyama H, Su SB, Mukaida N, Iwano M, Dohi K, et al. Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis. Kidney Int. 1996;49(3):761–767. doi: 10.1038/ki.1996.105 8648917

27. Yokoyama H, Wada T, Furuichi K, Segawa C, Shimizu M, Kobayashi K, et al. Urinary levels of chemokines (MCAF/MCP-1, IL-8) reflect distinct disease activities and phases of human IgA nephropathy. J Leukoc Biol. 1998;63(4):493–499. doi: 10.1002/jlb.63.4.493 9544580

28. Wada T, Furuichi K, Sakai N, Iwata Y, Yoshimoto K, Shimizu M, et al. Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int. 2000;58(4):1492–1499. doi: 10.1046/j.1523-1755.2000.00311.x 11012884

29. Kato S, Luyckx VA, Ots M, Lee KW, Ziai F, Troy JL, et al. Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. Kidney Int. 1999;56(3):1037–1048. doi: 10.1046/j.1523-1755.1999.00643.x 10469372

30. Sassy-Prigent C, Heudes D, Mandet C, Belair MF, Michel O, Perdereau B, et al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes. 2000;49(3):466–475. doi: 10.2337/diabetes.49.3.466 10868970

31. Kang YS, Lee MH, Song HK, Ko GJ, Kwon OS, Lim TK, et al. CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice. Kidney Int. 2010;78(9):883–894. doi: 10.1038/ki.2010.263 20686445

32. Sayyed SG, Ryu M, Kulkarni OP, Schmid H, Lichtnekert J, Gruner S, et al. An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int. 2011;80(1):68–78. doi: 10.1038/ki.2011.102 21508925

33. Seok SJ, Lee ES, Kim GT, Hyun M, Lee JH, Chen S, et al. Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. Nephrol Dial Transplant. 2013;28(7):1700–1710. doi: 10.1093/ndt/gfs555 23794669

34. Tarabra E, Giunti S, Barutta F, Salvidio G, Burt D, Deferrari G, et al. Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes. 2009;58(9):2109–2118. doi: 10.2337/db08-0895 19587356

35. Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol. 2008;294(4):F697–701. doi: 10.1152/ajprenal.00016.2008 18272603

36. Kanamori H, Matsubara T, Mima A, Sumi E, Nagai K, Takahashi T, et al. Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy. Biochem Biophys Res Commun. 2007;360(4):772–777. doi: 10.1016/j.bbrc.2007.06.148 17631861

37. Ruggiero C, Ehrenshaft M, Cleland E, Stadler K. High-fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production. Am J Physiol Endocrinol Metab. 2011;300(6):E1047–1058. doi: 10.1152/ajpendo.00666.2010 21386058

38. Sullivan T, Miao Z, Dairaghi DJ, Krasinski A, Wang Y, Zhao BN, et al. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am J Physiol Renal Physiol. 2013;305(9):F1288–F1297. doi: 10.1152/ajprenal.00316.2013 23986513

39. Eddy AA. Interstitial macrophages as mediators of renal fibrosis. Exp Nephrol. 1995;3(2):76–79. 7773640

40. Kluth DC, Erwig LP, Rees AJ. Multiple facets of macrophages in renal injury. Kidney Int. 2004;66(2):542–557. doi: 10.1111/j.1523-1755.2004.00773.x 15253705

41. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–1808. doi: 10.1172/JCI19246 14679176

42. Kim HM, Lee ES, Lee BR, Yadav D, Kim YM, Ko HJ, et al. C-C chemokine receptor 2 inhibitor ameliorates hepatic steatosis by improving ER stress and inflammation in a type 2 diabetic mouse model. PLoS One. 2015;10(3):e0120711. doi: 10.1371/journal.pone.0120711 25816097

43. Porter LE, Hollenberg NK. Obesity, salt intake, and renal perfusion in healthy humans. Hypertension. 1998;32(1):144–148. doi: 10.1161/01.hyp.32.1.144 9674651

44. Lee EY, Chung CH, Khoury CC, Yeo TK, Pyagay PE, Wang A, et al. The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-beta, increases podocyte motility and albumin permeability. Am J Physiol Renal Physiol. 2009;297(1):F85–94. doi: 10.1152/ajprenal.90642.2008 19420107

45. Valensi P, Assayag M, Busby M, Paries J, Lormeau B, Attali JR. Microalbuminuria in obese patients with or without hypertension. Int J Obes Relat Metab Disord. 1996;20(6):574–579. 8782735

46. Borradaile NM, Han X, Harp JD, Gale SE, Ory DS, Schaffer JE. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J Lipid Res. 2006;47(12):2726–2737. doi: 10.1194/jlr.M600299-JLR200 16960261

47. Kitamura M. Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces. Am J Physiol Renal Physiol. 2008;295(2):F323–334. doi: 10.1152/ajprenal.00050.2008 18367660

48. Min SY, Ha DS, Ha TS. Puromycin aminonucleoside triggers apoptosis in podocytes by inducing endoplamic reticulum stress: Kidney Res Clin Pract. 2018;37:210–221. doi: 10.23876/j.krcp.2018.37.3.210 30254845

49. Ahn N, Kim K. Combined influence of dietary restriction and treadmill running on MCP-1 and the expression of oxidative stress-related mRNA in the adipose tissue in obese mice. J Exerc Nutrition Biochem. 2014;18(3):311–318. doi: 10.5717/jenb.2014.18.3.311 25566468

50. Munusamy S, do Carmo JM, Hosler JP, Hall JE. Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin. Am J Physiol Renal Physiol. 2015;309(8):F731–743. doi: 10.1152/ajprenal.00188.2015 26290368

51. Gargalovic PS, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol. 2006;26(11):2490–2496. doi: 10.1161/01.ATV.0000242903.41158.a1 16931790


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