Abstracts
C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5−/−) and wild-type (CCR5+/+) mice, both aged about 10 months, had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg). Compared with CCR5+/+ mice, CCR5−/− mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5−/− mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5−/− mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β were also significantly increased in the kidney of CCR5−/− mice after LPS challenge. Moreover, primary kidney cells from CCR5−/− mice showed greater increases in TNF-α production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-α production and apoptosis in the primary kidney cells from CCR5−/− mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-α following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- CCR5:
-
C-C chemokine receptor 5
- LPS:
-
Lipopolysaccharide
- TNF-α:
-
Tumor necrosis factor alpha
- IL:
-
Interleukin
- ICAM-1:
-
Intercellular adhesion molecule 1
- BUN:
-
Blood urea nitrogen
- CCR5+/+ mice:
-
Wild-type mice
- CCR5−/− mice:
-
CCR5 knockout mice
- TUNEL:
-
Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
References
Akcay A, Nguyen Q, Edelstein CL (2009) Mediators of inflammation in acute kidney injury. Mediat Inflamm 2009:137072. doi:10.1155/2009/137072
Albelda SM, Smith CW, Ward PA (1994) Adhesion molecules and inflammatory injury. FASEB J 8(8):504–512
Anders HJ, Vielhauer V, Frink M et al (2002) A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest 109(2):251–259. doi:10.1172/JCI14040
Barcellos LF, Schito AM, Rimmler JB et al (2000) CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Multiple sclerosis genetics group. Immunogenetics 51(4–5):281–288
Broide DH, Humber D, Sullivan S, Sriramarao P (1998) Inhibition of eosinophil rolling and recruitment in P-selectin- and intracellular adhesion molecule-1-deficient mice. Blood 91(8):2847–2856
Coenen M, Nattermann J (2010) The role of CCR5 in HCV infection. Eur J Med Res 15(3):97–101
Cunningham PN, Dyanov HM, Park P, Wang J, Newell KA, Quigg RJ (2002) Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney. J Immunol 168(11):5817–5823
Cunningham PN, Wang Y, Guo R, He G, Quigg RJ (2004) Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J Immunol 172(4):2629–2635
Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N (2000) Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol 156(6):1951–1959. doi:10.1016/S0002-9440(10)65068-7
Day YJ, Huang L, Ye H, Linden J, Okusa MD (2005) Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am J Physiol Renal Physiol 288(4):F722–F731. doi:10.1152/ajprenal.00378.2004
Dong Z, Atherton SS (2007) Tumor necrosis factor-alpha in cisplatin nephrotoxicity: a homebred foe? Kidney Int 72(1):5–7. doi:10.1038/sj.ki.5002320
Fadel SA, Bromley SK, Medoff BD, Luster AD (2008) CXCR3-deficiency protects influenza-infected CCR5-deficient mice from mortality. Eur J Immunol 38(12):3376–3387. doi:10.1002/eji.200838628
Fantuzzi G, Zheng H, Faggioni R et al (1996) Effect of endotoxin in IL-1 beta-deficient mice. J Immunol 157(1):291–296
Fattori E, Della Rocca C, Costa P et al (1994) Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 83(9):2570–2579
Faubel S, Ljubanovic D, Reznikov L, Somerset H, Dinarello CA, Edelstein CL (2004) Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis. Kidney Int 66(6):2202–2213. doi:10.1111/j.1523-1755.2004.66010.x
Furuichi K, Wada T, Iwata Y et al (2003) CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol 14(10):2503–2515
Furuichi K, Gao JL, Horuk R, Wada T, Kaneko S, Murphy PM (2008) Chemokine receptor CCR1 regulates inflammatory cell infiltration after renal ischemia-reperfusion injury. J Immunol 181(12):8670–8676
Gadient RA, Patterson PH (1999) Leukemia inhibitory factor, Interleukin 6, and other cytokines using the GP130 transducing receptor: roles in inflammation and injury. Stem Cells 17(3):127–137. doi:10.1002/stem.170127
Homsi E, Ribeiro-Alves MA, Lopes de Faria JB, Dias EP (2002) Interleukin-6 stimulates tubular regeneration in rats with glycerol-induced acute renal failure. Nephron 92(1):192–199
Jo SK, Cho WY, Sung SA, Kim HK, Won NH (2005) MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis. Kidney Int 67(2):458–466. doi:10.1111/j.1523-1755.2005.67102.x
Kayama F, Yoshida T, Elwell MR, Luster MI (1995) Cadmium-induced renal damage and proinflammatory cytokines: possible role of IL-6 in tubular epithelial cell regeneration. Toxicol Appl Pharmacol 134(1):26–34. doi:10.1006/taap.1995.1165
Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV (1994) Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci U S A 91(2):812–816
Knotek M, Rogachev B, Wang W et al (2001) Endotoxemic renal failure in mice: role of tumor necrosis factor independent of inducible nitric oxide synthase. Kidney Int 59(6):2243–2249. doi:10.1046/j.1523-1755.2001.00740.x
Lee YK, Kwak DH, Oh KW et al (2009) CCR5 deficiency induces astrocyte activation, Abeta deposit and impaired memory function. Neurobiol Learn Mem 92(3):356–363. doi:10.1016/j.nlm.2009.04.003
Li L, Huang L, Sung SS et al (2007) NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol 178(9):5899–5911
Linas SL, Shanley PF, Whittenburg D, Berger E, Repine JE (1988) Neutrophils accentuate ischemia-reperfusion injury in isolated perfused rat kidneys. Am J Physiol 255(4 Pt 2):F728–F735
Mehta RL, Kellum JA, Shah SV et al (2007) Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11(2):R31. doi:10.1186/cc5713
Meldrum KK, Meldrum DR, Hile KL et al (2001) p38 MAPK mediates renal tubular cell TNF-alpha production and TNF-alpha-dependent apoptosis during simulated ischemia. Am J Physiol Cell Physiol 281(2):C563–C570
Messmer UK, Briner VA, Pfeilschifter J (1999) Tumor necrosis factor-alpha and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells. Kidney Int 55(6):2322–2337. doi:10.1046/j.1523-1755.1999.00473.x
Mishima K, Baba A, Matsuo M, Itoh Y, Oishi R (2006) Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity. Free Radic Biol Med 40(9):1564–1577. doi:10.1016/j.freeradbiomed.2005.12.025
Moreno C, Gustot T, Nicaise C et al (2005) CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice. Hepatology 42(4):854–862. doi:10.1002/hep.20865
Patel NS, Chatterjee PK, Di Paola R et al (2005) Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion. J Pharmacol Exp Ther 312(3):1170–1178. doi:10.1124/jpet.104.078659
Perez de Lema G, Maier H, Franz TJ et al (2005) Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice. J Am Soc Nephrol 16(12):3592–3601. doi:10.1681/ASN.2005040426
Ramesh G, Reeves WB (2002) TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110(6):835–842. doi:10.1172/JCI15606
Ramesh G, Reeves WB (2003) TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am J Physiol Renal Physiol 285(4):F610–F618. doi:10.1152/ajprenal.00101.2003
Ramesh G, Reeves WB (2005) p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 289(1):F166–F174. doi:10.1152/ajprenal.00401.2004
Ramesh G, Kimball SR, Jefferson LS, Reeves WB (2007) Endotoxin and cisplatin synergistically stimulate TNF-alpha production by renal epithelial cells. Am J Physiol Renal Physiol 292(2):F812–F819. doi:10.1152/ajprenal.00277.2006
Remick DG, Newcomb DE, Bolgos GL, Call DR (2000) Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13(2):110–116
Russell JA, Singer J, Bernard GR et al (2000) Changing pattern of organ dysfunction in early human sepsis is related to mortality. Crit Care Med 28(10):3405–3411
Rybak SL, Murphy RF (1998) Primary cell cultures from murine kidney and heart differ in endosomal pH. J Cell Physiol 176(1):216–222. doi:10.1002/(SICI)1097-4652(199807)176:1<216:AID-JCP23>3.0.CO
Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M (1996) Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 35(11):3362–3367. doi:10.1021/bi952950g
Schrier RW, Wang W (2004) Acute renal failure and sepsis. N Engl J Med 351(2):159–169. doi:10.1056/NEJMra032401351/2/159
Segerer S, Nelson PJ, Schlondorff D (2000) Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol 11(1):152–176
Segerer S, Banas B, Wornle M et al (2004) CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. Am J Pathol 164(2):635–649. doi:10.1016/S0002-9440(10)63152-5
Sorce S, Bonnefont J, Julien S et al (2010) Increased brain damage after ischaemic stroke in mice lacking the chemokine receptor CCR5. Br J Pharmacol 160(2):311–321. doi:10.1111/j.1476-5381.2010.00697.x
Turner JE, Paust HJ, Steinmetz OM et al (2008) CCR5 deficiency aggravates crescentic glomerulonephritis in mice. J Immunol 181(9):6546–6556
Turner JE, Paust HJ, Bennstein SB et al (2012) Protective role for CCR5 in murine lupus nephritis. Am J Physiol Renal Physiol 302(11):F1503–F1515. doi:10.1152/ajprenal.00382.2011
Wang W, Faubel S, Ljubanovic D et al (2005) Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice. Am J Physiol Renal Physiol 288(5):F997–F1004. doi:10.1152/ajprenal.00130.2004
Xu C, Chang A, Hack BK, Eadon MT, Alper SL, Cunningham PN (2014) TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis. Kidney Int 85(1):72–81. doi:10.1038/ki.2013.286
Yanaba K, Mukaida N, Matsushima K, Murphy PM, Takehara K, Sato S (2004) Role of C-C chemokine receptors 1 and 5 and CCL3/macrophage inflammatory protein-1alpha in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production. Eur J Immunol 34(12):3553–3561. doi:10.1002/eji.200425426
Zhang D, Li Y, Liu Y, Xiang X, Dong Z (2013) Paclitaxel ameliorates lipopolysaccharide-induced kidney injury by binding myeloid differentiation protein-2 to block Toll-like receptor 4-mediated nuclear factor-kappaB activation and cytokine production. J Pharmacol Exp Ther 345(1):69–75. doi:10.1124/jpet.112.202481
Acknowledgments
This work was supported by the National Research Foundation of Korea [NRF] grant funded by the Korea government (MSIP) [Grant Number MRC.2008-0062275 and 2015R1A2A2A09001137].
Conflict of interest
The authors declare that there is no duality of interest associated with this manuscript.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Lee, D.H., Park, M.H., Hwang, C.J. et al. CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury. Arch Toxicol 90, 1151–1162 (2016). https://doi.org/10.1007/s00204-015-1530-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-015-1530-9