Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The lupus-susceptibility gene kallikrein downmodulates antibody-mediated glomerulonephritis

Genes & Immunity volume 10, pages 503–508 (2009)Cite this article

Abstract

Sle3 is a NZM2410/NZW-derived lupus-susceptibility interval on murine chromosome 7, which is associated with spontaneous lupus nephritis (SLN), and also anti-GBM-induced glomerulonephritis (GN). The tissue kallikrein gene cluster is located within the Sle3 interval and constitutes potential candidate genes for this locus. We have recently reported that renal kallikrein expression was upregulated by anti-GBM antibody challenge in a strain-specific manner and that it was significantly underexpressed in the anti-GBM-sensitive strains, including B6.Sle3. Further sequencing and functional studies reported earlier provided evidence that kallikreins could constitute disease genes in lupus. In this report, we have used an adenoviral vector to deliver the klk1 gene to B6.Sle3 congenics to directly test if kallikreins might have a protective effect against anti-GBM-induced nephritis. Our data show that klk1 gene delivery ameliorated anti-GBM-induced nephritis in B6.Sle3 congenics. Taken together with earlier studies, these findings indicate that kallikreins play an important protective role in autoantibody-initiated GN and could constitute potential candidate genes for anti-GBM-induced GN and SLN.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Hahn BH . Antibodies to DNA. N Engl J Med 1998; 338: 1359–1368.

    Article  CAS  Google Scholar 

  2. Pisetsky DH . Anti-DNA and autoantibodies. Curr Opin Rheumatol 2000; 12: 364–368.

    Article  CAS  Google Scholar 

  3. Kotzin JB . Systemic lupus erythematosus. Cell 1996; 85: 303–306.

    Article  CAS  Google Scholar 

  4. Lefkowith JB, Gilkeson GS . Nephritogenic autoantibodies in lupus: current concepts and continuing controversies. Arthritis Rheum 1996; 39: 894–903.

    Article  CAS  Google Scholar 

  5. Foster MH, Kelley VR . Lupus nephritis: update on pathogenesis and disease mechanisms. Semin Nephrol 1999; 19: 173–181.

    CAS  Google Scholar 

  6. Vyse TJ, Kotzin BL . Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol 1998; 16: 261–292.

    Article  CAS  Google Scholar 

  7. Kono DH, Theofilopoulos AN . Genetics of systemic autoimmunity in mouse model of lupus. Int Rev Immunol 2000; 19: 367–387.

    Article  CAS  Google Scholar 

  8. Nose M, Nishihara M, Kamogawa J, Terada M, Nakatsuru S . Genetic basis of autoimmune disease in MRL/lpr mice: dissection of the complex pathological manifestations and their susceptibility loci. Rev in Immunogenetics 2000; 2: 154–164.

    CAS  Google Scholar 

  9. Fu Y, Yong D, Mohan C . The experimental anti-GBM model as a tool for studying spontaneous lupus nephritis. Clin Immunol 2007; 124: 109–118.

    Article  CAS  Google Scholar 

  10. Xie C, Zhou JX, Mohan C . Enhanced susceptibility to nephritis in the lupus facilitating NZW strain. Arthritis Rheum 2003; 48: 1080–1092.

    Article  CAS  Google Scholar 

  11. Xie C, Ruchi Sharma R, Wang H, Zhou XJ, Mohan C . Strain distribution pattern of susceptibility to immune-mediated nephritis. J Immunol 2004; 172: 5047–5055.

    Article  CAS  Google Scholar 

  12. Xie C, Gong Y, Qin X, Bhaskarabhatla M, Zhou XJ, Mohan C . Strain distribution pattern of immune nephritis–a follow-up study. Int Immunol 2008; 20: 719–728.

    Article  CAS  Google Scholar 

  13. Mohan C . Murine lupus genetics: lessons learned. Curr Opin Rheumatol 2001; 13: 352–360.

    Article  CAS  Google Scholar 

  14. Wakeland EK . Genetic dissection of systemic lupus erythematosus. Curr Opin Immunol 2000; 11: 701–707.

    Article  Google Scholar 

  15. Morel L, Mohan C, Yu Y, Croker BP, Tian N, Deng A et al. Functional dissection of SLE pathogenesis using congenic mouse strains. J Immunol 1997; 158: 6019–6028.

    CAS  Google Scholar 

  16. Mohan C, Yu Y, Morel L, Yang P, Wakeland EK . Genetic dissection of SLE pathogensis: Sle2 on murine chromosome 4 leads to B-cell hyperactivity. J Immunol 1997; 159: 454.

    CAS  Google Scholar 

  17. Mohan C, Alas E, Morel L, Yang P, Wakeland EK . Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. J Clin Invest 1998; 101: 1362.

    Article  CAS  Google Scholar 

  18. Mohan C, Morel L, Yang P, Wakeland EK . Accumulation of splenic B1a cells with potent antigen-presenting capability in NZM2410 lupus-prone mice. Arthritis Rheum 1998; 41: 1652–1662.

    Article  CAS  Google Scholar 

  19. Mohan C, Yu Y, Morel L, Yang P, Wakeland EK . Genetic dissection of SLE pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation and cell death. J Immunol 1999; 162: 6492–6502.

    CAS  Google Scholar 

  20. Morel L, Blenman KR, Croker BP, Wakeland EK . The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. Proc Natl Acad Sci USA 2001; 98: 1787–1792.

    Article  CAS  Google Scholar 

  21. Morel L, Tian XH, Croker BP, Wakeland EK . Epistatic modifiers of autoimmunity in a murine model of lupus nephritis. Immunity 1999; 11: 131–139.

    Article  CAS  Google Scholar 

  22. Sobel ES, Morel L, Baert R, Mohan C, Schiffenbauer J, Wakeland EK . Genetic dissection of SLE pathogenesis: evidence for functional expression expression of Sle3/5 in non-T-cells. J Immunol 2002; 169: 4025–4032.

    Article  CAS  Google Scholar 

  23. Mohan C, Morel L, Yang P, Watanabe H, Croker B, Gilkeson G et al. Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies. J Clin Invest 1999; 103: 1685.

    Article  CAS  Google Scholar 

  24. Morel L, Croker BP, Blenman KR, Mohan C, Huang G, Gilkeson G et al. Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc Natl Acad Sci USA 2000; 97: 6670–6675.

    Article  CAS  Google Scholar 

  25. Morel L, Yu Y, Blenman KR, Caldwell RA, Wakeland EK . Production of congenic mouse strains carrying SLE-susceptibility genes derived from the SLE-prone NZM/Aeg2410 strain. Mamm Genome 1996; 7: 335–339.

    Article  CAS  Google Scholar 

  26. Liu K, Li QZ, Yu Y, Liang C, Subramanian S, Zeng Z et al. Sle3 and Sle5 can independently couple with Sle1 to mediate severe lupus nephritis. Genes Immun 2007; 8: 634–645.

    Article  CAS  Google Scholar 

  27. Liu K, Li QZ, Delgado-Vega AM, Abelson AK, Sanchez E, Kelly JA et al. Kallikreins as disease genes in anti-GBM disease and lupus nephritis. J Clin Invest (in press).

  28. Moodley D, Naicker S . Tissue kallikrein excretion in acute and chronic renal transplant rejection. Immunopharmacology 1996; 33: 380–382.

    Article  CAS  Google Scholar 

  29. Zhou XJ, Laszik Z, Wang XQ, Silva FG, Vaziri ND . Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis. Lab Invest 2000; 80: 1905.

    Article  CAS  Google Scholar 

  30. Chao J, Bledsoe G, Yin H, Chao L . The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction. Biol Chem 2006; 387: 665–675.

    Article  CAS  Google Scholar 

  31. Chao J, Chao L . Kallikrein-kinin in stroke, cardiovascular and renal disease. Exp Physiol 2004; 90: 291–298.

    Article  Google Scholar 

  32. Chao J, Zhang J, Lin KF, Chao L . Adenovirus-mediated kallikrein gene delivery attenuates hypertension, cardiac hypertrophy and renal injury in Dahl Salt-sensitive rat. Hum Gene Therapy 1998; 9: 1–31.

    Article  Google Scholar 

  33. Chao J, Zhang J, Lin KF, Chao L . Adenovirus-mediated kallikrein gene delivery reverses salt-induced renal injury in Dahl salt-sensitive rats. Kidney Int 1998; 54: 1250–1260.

    Article  CAS  Google Scholar 

  34. Bledsoe G, Crickman S, Mao J, Xia CF, Murakami H, Chao L et al. Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis. Nephrol Dial Transplant 2006; 21: 624–633.

    Article  CAS  Google Scholar 

  35. Bledsoe G, Shen B, Yao Y, Zhang JJ, Chao L, Chao J . Reversal of renal fibrosis, inflammation,and glomerular hypertrophy by kallikrein gene delivery. Hum Gene Therapy 2006; 17: 545–555.

    Article  CAS  Google Scholar 

  36. Zhang JJ, Bledsoe G, Kato K, Chao L, Chao J . Tissue kalliakrein attenuates salt-induced renal fibrosis by inhibition of oxidative stree. Kidney Int 2004; 66: 732–733.

    Google Scholar 

  37. Schanstra JP, Neau E, Drogoz P, Gomez MAA, Novoa JML, Calise D et al. In vivo bradykinin B2 receptor activation reduces renal fibrosis. J Clin Invest 2002; 110: 371–379.

    Article  CAS  Google Scholar 

  38. Kakoki M, Takahashi N, Charles J, Smithies O . Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. Proc Natl Acad Sci USA 2004; 101: 13302–13305.

    Article  CAS  Google Scholar 

  39. Chao J, Li HJ, Yao YY, Shen B, Gao L, Bledsoe G et al. Kinin infusion prevents renal inflammation, apoptosis, and fibrosis via inhibition of oxidative stress and mitogen-activated protein kinase activity. Hypertension 2007; 49: 490–497.

    Article  CAS  Google Scholar 

  40. Bhoola KD, Figueroa CD, Worthy K . Bioregualtion of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992; 44: 1–80.

    CAS  PubMed  Google Scholar 

  41. Carretero OA, Scicli AG . The renal kallikrein-kinin system. Am J Physiol 1980; 238: F247–F255.

    CAS  PubMed  Google Scholar 

  42. Regoli D, Rhaleb NE, Drapeau G, Dion S . Kinin receptor subtypes. J Cardiovasc Pharmacol 1990; 15: S30–S38.

    Article  CAS  Google Scholar 

  43. Mason AJ, Evans BA, Cox DR, Shine J, Richards RI . Structure of mouse kallikrein gene family suggests a role in specific processing of biologically active peptides. Nature 1983; 303: 300–307.

    Article  CAS  Google Scholar 

  44. Hong Fu, Jing Li, Li QX, Xia L, Shao L . Protective effect of ligustrazine on accelerated anti-glomerular basement membrane antibody nephritis in rats is based on its antioxidant properties. Eur J Pharmacol 2007; 563: 197–202.

    Article  Google Scholar 

  45. Wolf WC, Yoshida H, Agata J, Chao L, Chao J . Human tissue kallikrein gene delivery attenuates hypertension, renal injury, and cardiac remodeling in chronic renal failure. Kidney Int 2000; 58: 730–739.

    Article  CAS  Google Scholar 

  46. Eddy AA, McCulloch LM, Adams JA . Intraglomerular leukocyte recruitment during nephrotoxic serum nephritis in rats. Clin Immunol Immunopathol 1990; 57: 441–458.

    Article  CAS  Google Scholar 

  47. Basnakian AG, Kaushal GP, Shah SV . Apoptotic pathways of oxidative damage to renal tubular epithelial cells. Antioxid Redox Signal 2002; 4: 915–924.

    Article  CAS  Google Scholar 

  48. Sha SH, Schacht J . Formation of reactive oxygen species following bioactivation of gentamicin. Free Radic Biol Med 1999; 26: 341–347.

    Article  CAS  Google Scholar 

  49. Stambe C, Atkins RC, Hill PA, Nikolic-Paterson DJ . Activation and cellular localization of the p38 and JNK MAPK pathways in rat crescentic glomerulonephritis. Kidney Int 2003; 64: 2121–2132.

    Article  CAS  Google Scholar 

  50. Datta PK, Sharma M, Duann P, Lianos EA . Effect of nitric oxide synthase inhibition on proteinuria in glomerular immune injury. Exp Biol Med 2006; 231: 576–584.

    Article  CAS  Google Scholar 

  51. Ikezumi Y, Hurst L, Atkins RC, Nikolic-Paterson DJ . Macrophage-mediated renal injury is dependent on signaling via the JNK pathway. J Am Soc Nephrol 2004; 15: 1775–1784.

    Article  CAS  Google Scholar 

  52. Rana A, Sathyanarayana P, Lieberthal W . Role of apoptosis of renal tubular cells in acute renal failure: therapeutic implications. Apoptosis 2001; 6: 83–102.

    Article  CAS  Google Scholar 

  53. Bledsoe G, Shen B, Yao YY, Hagiwara M, Mizell B, Teuton M et al. Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury. Toxicol Sci 2008; 102: 433–443.

    Article  CAS  Google Scholar 

  54. Linz W, Wiemer G, Gohlke P, Unger T, Schölkens BA . Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995; 47: 25–49.

    CAS  Google Scholar 

  55. Erdös EG, Deddish PA, Marcic BM . Potentiation of bradykinin actions by ACE inhibitors. Trends Endocrinol Metab 1999; 10: 223–229.

    Article  Google Scholar 

  56. Tschöpe C, Seidl U, Reinecke A, Riester U, Graf K, Schultheiss HP et al. Kinins are involved in the antiproteinuric effect of angiotensin-converting enzyme inhibition in experimental diabetic nephropathy. Int Immunopharmacol 2003; 3: 335–344.

    Article  Google Scholar 

  57. Schmaier AH . The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction. Am J Physiol Regul Integr Comp Physiol 2003; 285: R1–R13.

    Article  CAS  Google Scholar 

  58. Buleon M, Allard J, Jaafar A, Praddaude F, Dickson Z, Ranera M-T et al. Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model. Am J Physiol Renal Physiol 2008; 294: F1249–F1256.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Q-Z Li, J Zhou, R Yang, Q Ye, K Liu, S Liu, X Shao, L Li, E K Wakeland & C Mohan

  2. Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Q-Z Li, M Yan & C Mohan

  3. Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    X-J Zhou

Authors
  1. Q-Z Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Q Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. X Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. X-J Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E K Wakeland
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C Mohan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Q-Z Li or C Mohan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, QZ., Zhou, J., Yang, R. et al. The lupus-susceptibility gene kallikrein downmodulates antibody-mediated glomerulonephritis. Genes Immun 10, 503–508 (2009). https://doi.org/10.1038/gene.2009.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2009.7

Keywords

This article is cited by

Search

Advanced search

Quick links