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Journal of Molecular Medicine

, Volume 94, Issue 4, pp 443–455 | Cite as

CD4 T cell knockout does not protect against kidney injury and worsens cancer

  • Kameswaran Ravichandran
  • Qian Wang
  • Abdullah Ozkok
  • Alkesh Jani
  • Howard Li
  • Zhibin He
  • Danica Ljubanovic
  • Mary C. Weiser-Evans
  • Raphael A. Nemenoff
  • Charles L. EdelsteinEmail author
Original Article

Abstract

Most previous studies of cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose cisplatin administration that leads to mortality in non-tumor-bearing mice. The aim of the study was to determine whether CD4 T cell knockout protects against AKI and cancer in a clinically relevant model of low-dose cisplatin-induced AKI in mice with cancer. Kidney function, serum neutrophil gelatinase-associated lipocalin (NGAL), acute tubular necrosis (ATN), and tubular apoptosis score were the same in wild-type and CD4 −/− mice with AKI. The lack of protection against AKI in CD4 −/− mice was associated with an increase in extracellular signal-regulated kinase (ERK), p38, CXCL1, and TNF-α, mediators of AKI and fibrosis, in both cisplatin-treated CD4 −/− mice and wild-type mice. The lack of protection was independent of the presence of cancer or not. Tumor size was double, and cisplatin had an impaired therapeutic effect on the tumors in CD4 −/− vs. wild-type mice. Mice depleted of CD4 T cells using the GK1.5 antibody were not protected against AKI and had larger tumors and lesser response to cisplatin. In summary, in a clinically relevant model of cisplatin-induced AKI in mice with cancer, (1) CD4 −/− mice were not protected against AKI; (2) ERK, p38, CXCL1, and TNF-α, known mediators of AKI, and interstitial fibrosis were increased in CD4 −/− kidneys; and (3) CD4 −/− mice had faster tumor growth and an impaired therapeutic effect of cisplatin on the tumors. The data warns against the use of CD4 T cell inhibition to attenuate cisplatin-induced AKI in patients with cancer.

Key message

  • A clinically relevant low-dose cisplatin model of AKI in mice with cancer was used.

  • CD4 −/− mice were not functionally or histologically protected against AKI.

  • CD4 −/− mice had faster tumor growth.

  • CD4 −/− mice had an impaired therapeutic effect of cisplatin on the tumors.

  • Mice depleted of CD4 T cells were not protected against AKI and had larger tumors.

Keywords

CD4 T cell Kidney Cancer 

Notes

Acknowledgments

This work was support by a Veterans Affairs Merit award [1I01BX001737-01A1] to C.L.E. AO was supported by the International Society of Nephrology and the Turkish Society of Nephrology.

Compliance with ethical standards

All experiments were conducted with adherence to the NIH Guide for the Care and Use of Laboratory Animals. The animal protocol was approved by the Animal Care and Use Committee of the University of Colorado at Denver.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

109_2015_1366_MOESM1_ESM.docx (601 kb)
ESM 1 (DOCX 600 kb)

References

  1. 1.
    Ozkok A, Edelstein CL (2014) Pathophysiology of cisplatin-induced acute kidney injury. Biomed Res IntGoogle Scholar
  2. 2.
    Faubel SG, Ljubanovic D, Reznikov LL, Somerset H, Dinarello CA, Edelstein CL (2004) Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis. Kidney Int 66:2202–2213CrossRefPubMedGoogle Scholar
  3. 3.
    Lu L, Oh DJ, Dursun B, He Z, Hoke TS, Faubel S, Edelstein CL (2007) Increased macrophage infiltration and fractalkine expression in cisplatin-induced acute renal failure in mice. J Pharmacol Exp Ther 324:111–117CrossRefPubMedGoogle Scholar
  4. 4.
    Faubel S, Lewis EC, Reznikov L, Ljubanovic D, Hoke TS, Somerset H, Oh DJ, Lu L, Klein CL, Dinarello CA et al (2007) Cisplatin-induced ARF is associated with an increase in the cytokines IL-1â, IL-18, IL-6 and neutrophil infiltration in the kidney. J Pharmacol Exp Ther 322:8–15CrossRefPubMedGoogle Scholar
  5. 5.
    Akcay A, Nguyen Q, He Z, Turkmen K, Lee D, Andres Hernando A, Altmann C, Toker A, Pacic A, Ljubanovic D et al (2011) IL-33 exacerbates acute kidney injury. J Am Soc Nephrol 22:2057–2067CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Liu M, Chien CC, Burne-Taney M, Molls RR, Racusen LC, Colvin RB, Rabb H (2006) A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. J Am Soc Nephol 17:765–774CrossRefGoogle Scholar
  7. 7.
    Lee H, Nho D, Chung HS, Lee H, Shin MK, Kim SH, Bae H (2010) CD4 + CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice. Kidney Int 78(11):1100–9CrossRefPubMedGoogle Scholar
  8. 8.
    Tennis MA, Van Scoyk M, Heasley LE, Vandervest K, Weiser-Evans M, Freeman S, Keith RL, Simpson P, Nemenoff RA, Winn RA (2010) Prostacyclin inhibits non-small cell lung cancer growth by a frizzled 9-dependent pathway that is blocked by secreted frizzled-related protein 1. Neoplasia 12:244–253CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wick M, Hurteau G, Dessev C, Chan D, Geraci MW, Winn RA, Heasley LE, Nemenoff RA (2002) Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth. Mol Pharmacol 62(5):1207–14CrossRefPubMedGoogle Scholar
  10. 10.
    Gobe G, Zhang XJ, Willgoss DA, Schoch E, Hogg NA, Endre ZH (2000) Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat. J Am Soc Nephrol 11:454–467PubMedGoogle Scholar
  11. 11.
    Farris AB, Adams CD, Brousaides N, Della Pelle PA, Collins AB, Moradi E, Smith RN, Grimm PC, Colvin RB (2011) Morphometric and visual evaluation of fibrosis in renal biopsies. J Am Soc Nephrol 22:176–186CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Dursun B, He Z, Somerset H, Oh DJ, Faubel S, Edelstein CL (2006) Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis. Am J Physiol Ren Physiol 291:F578–F587CrossRefGoogle Scholar
  13. 13.
    Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P (2004) Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 24(3):307–15CrossRefPubMedGoogle Scholar
  14. 14.
    Roncal CA, Mu W, Croker B, Reungjui S, Ouyang X, Tabah-Fisch I, Johnson RJ, Ejaz AA (2007) Effect of elevated serum uric acid on cisplatin-induced acute renal failure. Am J Physiol Ren Physiol 292(1):F116–22CrossRefGoogle Scholar
  15. 15.
    Ramesh G, Reeves WB (2002) TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110:835–842CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ysebaert DK, De Greef KE, Vercauteren SR, Ghielli M, Verpooten GA, Eyskens EJ, De Broe ME (2000) Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant 15:1562–1574CrossRefPubMedGoogle Scholar
  17. 17.
    Faubel SG, Ljubanovic D, Poole B, Dursun B, Cushing S, He Z, Gill RG, Edelstein CL (2005) Peripheral CD4 T cell depletion is not sufficient to prevent ischemic acute renal failure. Transplantation 80:643–649CrossRefPubMedGoogle Scholar
  18. 18.
    Ries F, Klastersky J (1986) Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 8:368–379CrossRefPubMedGoogle Scholar
  19. 19.
    Arunkumar PA, Viswanatha GL, Radheshyam N, Mukund H, Belliyappa MS (2012) Science behind cisplatin-induced nephrotoxicity in humans: a clinical study. Asian Pac J Trop Biomed 2:640–644CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Dentino M, Luft FC, Yum MN, Williams SD, Einhorn LH (1978) Long term effect of cis-diamminedichloride platinum (CDDP) on renal function and structure in man. Cancer 41:1274–1281CrossRefPubMedGoogle Scholar
  21. 21.
    Gretz N, Ceccherini I, Kranzlin B, Kloting I, Devoto M, Rohmeiss P, Hocher B, Waldherr R, Romeo G (1995) Gender-dependent disease severity in autosomal polycystic kidney disease of rats. Kidney Int 48:496–500CrossRefPubMedGoogle Scholar
  22. 22.
    Holmdahl R, Malissen B (2012) The need for littermate controls. Eur J Immunol 42:45–47CrossRefPubMedGoogle Scholar
  23. 23.
    Kim HJ, Ravichandran K, Ozkok A, Wang Q, He Z, Jani A, Ljubanovic D, Douglas IS, Edelstein CL (2014) The water-soluble triptolide derivative PG490-88 protects against cisplatin-induced acute kidney injury. J Pharmacol Exp Ther 349:518–525CrossRefPubMedGoogle Scholar
  24. 24.
    Ramesh G, Reeves WB (2005) p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Ren Physiol 289:F166–F174CrossRefGoogle Scholar
  25. 25.
    Benedetti G, Fredriksson L, Herpers B, Meerman J, Van de Water B, De GM (2013) TNF-alpha-mediated NF-kappaB survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells. Biochem Pharmacol 85:274–286CrossRefPubMedGoogle Scholar
  26. 26.
    Hu HM, Winter H, Urba WJ, Fox BA (2000) Divergent roles for CD4+ T cells in the priming and effector/memory phases of adoptive immunotherapy. J Immunol 165:4246–4253CrossRefPubMedGoogle Scholar
  27. 27.
    Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368:1845–1846CrossRefPubMedGoogle Scholar
  28. 28.
    Giuliani CM, Dass CR (2013) Autophagy and cancer: taking the ‘toxic’ out of cytotoxics. J Pharm Pharmacol 65:777–789CrossRefPubMedGoogle Scholar
  29. 29.
    Intlekofer AM, Thompson CB (2013) At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol 94:25–39CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L et al (2004) Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 101:17174–17179CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Kameswaran Ravichandran
    • 1
  • Qian Wang
    • 1
  • Abdullah Ozkok
    • 1
  • Alkesh Jani
    • 1
  • Howard Li
    • 1
  • Zhibin He
    • 1
  • Danica Ljubanovic
    • 2
  • Mary C. Weiser-Evans
    • 1
  • Raphael A. Nemenoff
    • 1
  • Charles L. Edelstein
    • 1
    Email author
  1. 1.Division of Renal Diseases and HypertensionUniv. of Colorado at DenverAuroraUSA
  2. 2.University Hospital DubravaZagrebCroatia

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