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.

  • Review Article
  • Published:

Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

Nature Reviews Nephrology volume 11, pages 642–655 (2015)Cite this article

Subjects

Key Points

  • The innate immune system is essential for preventing urinary tract infection (UTI) and limiting the spread of infection

  • Urinary antimicrobial peptides exhibit bactericidal and bacteriostatic activity toward uropathogenic bacteria

  • Intercalated cells are the major renal source of antimicrobial peptides

  • Antimicrobial peptides possess immunomodulatory activity in addition to antimicrobial activity

  • Urinary antimicrobial peptides have diagnostic and therapeutic potential for patients with UTIs

Abstract

Urinary tract infections (UTIs), including pyelonephritis, are among the most common and serious infections encountered in nephrology practice. UTI risk is increased in selected patient populations with renal and urinary tract disorders. As the prevalence of antibiotic-resistant uropathogens increases, novel and alternative treatment options will be needed to reduce UTI-associated morbidity. Discoveries over the past decade demonstrate a fundamental role for the innate immune system in protecting the urothelium from bacterial challenge. Antimicrobial peptides, an integral component of this urothelial innate immune system, demonstrate potent bactericidal activity toward uropathogens and might represent a novel class of UTI therapeutics. The urothelium of the bladder and the renal epithelium secrete antimicrobial peptides into the urinary stream. In the kidney, intercalated cells—a cell-type involved in acid–base homeostasis—have been shown to be an important source of antimicrobial peptides. Intercalated cells have therefore become the focus of new investigations to explore their function during pyelonephritis and their role in maintaining urinary tract sterility. This Review provides an overview of UTI pathogenesis in the upper and lower urinary tract. We describe the role of intercalated cells and the innate immune response in preventing UTI, specifically highlighting the role of antimicrobial peptides in maintaining urinary tract sterility.

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: An overview of the innate and adaptive immune systems.
Figure 2: Innate immune mechanisms in the urothelium.
Figure 3: Antimicrobial peptides produced in the various components of the human urinary tract.
Figure 4: Antimicrobial peptides are produced by the renal tubules.
Figure 5: Antimicrobial activities associated with antimicrobial peptides.

Similar content being viewed by others

References

  1. Hooton, T. M. Clinical practice. Uncomplicated urinary tract infection. N. Engl. J. Med. 366, 1028–1037 (2012).

    CAS  PubMed  Google Scholar 

  2. Healthcare Cost and Utilization Project. National Inpatient Sample [online], (2012).

  3. Foxman, B., Barlow, R., D'Arcy, H., Gillespie, B. & Sobel, J. D. Urinary tract infection: self-reported incidence and associated costs. Ann. Epidemiol. 10, 509–515 (2000).

    CAS  PubMed  Google Scholar 

  4. Foxman, B. et al. Risk factors for second urinary tract infection among college women. Am. J. Epidemiol. 151, 1194–1205 (2000).

    CAS  PubMed  Google Scholar 

  5. Foxman, B. Recurring urinary tract infection: incidence and risk factors. Am. J. Public Health 80, 331–333 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Ronald, A. The etiology of urinary tract infection: traditional and emerging pathogens. Am. J. Med. 113 (Suppl. 1A), 14S–19S (2002).

    PubMed  Google Scholar 

  7. Mulvey, M. A., Schilling, J. D., Martinez, J. J. & Hultgren, S. J. Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses. Proc. Natl Acad. Sci. USA 97, 8829–8835 (2000).

    CAS  PubMed  Google Scholar 

  8. Becknell, B., Schober, M., Korbel, L. & Spencer, J. D. The diagnosis, evaluation and treatment of acute and recurrent pediatric urinary tract infections. Expert Rev. Anti Infect. Ther. 13, 81–90 (2015).

    CAS  PubMed  Google Scholar 

  9. Harrington, R. D. & Hooton, T. M. Urinary tract infection risk factors and gender. J. Gend. Specif. Med. 3, 27–34 (2000).

    CAS  PubMed  Google Scholar 

  10. Abbott, K. C. et al. Late urinary tract infection after renal transplantation in the United States. Am. J. Kidney Dis. 44, 353–362 (2004).

    PubMed  Google Scholar 

  11. Alangaden, G. J. et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin. Transplant. 20, 401–409 (2006).

    PubMed  Google Scholar 

  12. Pelle, G. et al. Acute pyelonephritis represents a risk factor impairing long-term kidney graft function. Am. J. Transplant. 7, 899–907 (2007).

    CAS  PubMed  Google Scholar 

  13. Zasloff, M. Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. J. Am. Soc. Nephrol. 18, 2810–2816 (2007).

    CAS  PubMed  Google Scholar 

  14. Spencer, J. D., Schwaderer, A. L., Becknell, B., Watson, J. & Hains, D. S. The innate immune response during urinary tract infection and pyelonephritis. Pediatr. Nephrol. 29, 1139–1149 (2013).

    PubMed  PubMed Central  Google Scholar 

  15. Hato, T. & Dagher, P. C. How the innate immune system senses trouble and causes trouble. Clin. J. Am. Soc. Nephrol. http://dx.doi.org/10.2215/CJN.04680514

  16. Jorgensen, I. & Seed, P. C. How to make it in the urinary tract: a tutorial by Escherichia coli. PLoS Pathog. 8, e1002907 (2012).

    PubMed  PubMed Central  Google Scholar 

  17. Justice, S. S., Harrison, A., Becknell, B. & Mason, K. M. Bacterial differentiation, development, and disease: mechanisms for survival. FEMS Microbiol. Lett. 360, 1–8 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Dhakal, B. K., Kulesus, R. R. & Mulvey, M. A. Mechanisms and consequences of bladder cell invasion by uropathogenic Escherichia coli. Eur. J. Clin. Invest. 38 (Suppl. 2), 2–11 (2008).

    CAS  PubMed  Google Scholar 

  19. Bishop, B. L. et al. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat. Med. 13, 625–630 (2007).

    CAS  PubMed  Google Scholar 

  20. Justice, S. S. et al. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc. Natl Acad. Sci. USA 101, 1333–1338 (2004).

    CAS  PubMed  Google Scholar 

  21. Hunstad, D. A. & Justice, S. S. Intracellular lifestyles and immune evasion strategies of uropathogenic Escherichia coli. Annu. Rev. Microbiol. 64, 203–221 (2010).

    CAS  PubMed  Google Scholar 

  22. Rosen, D. A., Hooton, T. M., Stamm, W. E., Humphrey, P. A. & Hultgren, S. J. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med. 4, e329 (2007).

    PubMed  PubMed Central  Google Scholar 

  23. Mysorekar, I. U. & Hultgren, S. J. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc. Natl Acad. Sci. USA 103, 14170–14175 (2006).

    CAS  PubMed  Google Scholar 

  24. Schilling, J. D., Lorenz, R. G. & Hultgren, S. J. Effect of trimethoprim-sulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic Escherichia coli. Infect. Immun. 70, 7042–7049 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chassin, C. et al. Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and independent inflammatory pathways. J. Immunol. 177, 4773–4784 (2006).

    CAS  PubMed  Google Scholar 

  26. Chassin, C., Tourneur, E., Bens, M. & Vandewalle, A. A role for collecting duct epithelial cells in renal antibacterial defences. Cell. Microbiol. 13, 1107–1113 (2011).

    CAS  PubMed  Google Scholar 

  27. Paragas, N. et al. α-Intercalated cells defend the urinary system from bacterial infection. J. Clin. Invest. 124, 2963–2976 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Pichon, C. et al. Uropathogenic Escherichia coli AL511 requires flagellum to enter renal collecting duct cells. Cell. Microbiol. 11, 616–628 (2009).

    CAS  PubMed  Google Scholar 

  29. Roberts, J. A. et al. The Gal(α1–4)Gal-specific tip adhesin of Escherichia coli P-fimbriae is needed for pyelonephritis to occur in the normal urinary tract. Proc. Natl Acad. Sci. USA 91, 11889–11893 (1994).

    CAS  PubMed  Google Scholar 

  30. Chassin, C. et al. TLR4 facilitates translocation of bacteria across renal collecting duct cells. J. Am. Soc. Nephrol. 19, 2364–2374 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Anderson, G. G., Goller, C. C., Justice, S., Hultgren, S. J. & Seed, P. C. Polysaccharide capsule and sialic acid-mediated regulation promote biofilm-like intracellular bacterial communities during cystitis. Infect. Immun. 78, 963–975 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Smith, Y. C., Rasmussen, S. B., Grande, K. K., Conran, R. M. & O'Brien, A. D. Hemolysin of uropathogenic Escherichia coli evokes extensive shedding of the uroepithelium and hemorrhage in bladder tissue within the first 24 hours after intraurethral inoculation of mice. Infect. Immun. 76, 2978–2990 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rippere-Lampe, K. E., O'Brien, A. D., Conran, R. & Lockman, H. A. Mutation of the gene encoding cytotoxic necrotizing factor type 1 (cnf(1)) attenuates the virulence of uropathogenic Escherichia coli. Infect. Immun. 69, 3954–3964 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ashkar, A. A., Mossman, K. L., Coombes, B. K., Gyles, C. L. & Mackenzie, R. FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which requires TLR4 and type 1 interferon signalling. PLoS Pathog. 4, e1000233 (2008).

    PubMed  PubMed Central  Google Scholar 

  35. Ragnarsdottir, B. et al. Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J. Infect. Dis. 196, 475–484 (2007).

    CAS  PubMed  Google Scholar 

  36. Weichhart, T., Haidinger, M., Horl, W. H. & Saemann, M. D. Current concepts of molecular defence mechanisms operative during urinary tract infection. Eur. J. Clin. Invest. 38 (Suppl. 2), 29–38 (2008).

    CAS  PubMed  Google Scholar 

  37. Hains, D. S. et al Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility. Am. J. Physiol. Renal Physiol. 307, F869–F880 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gauer, S. et al. IL-18 is expressed in the intercalated cell of human kidney. Kidney Int. 72, 1081–1087 (2007).

    CAS  PubMed  Google Scholar 

  39. Ali, A. S., Townes, C. L., Hall, J. & Pickard, R. S. Maintaining a sterile urinary tract: the role of antimicrobial peptides. J. Urol. 182, 21–28 (2009).

    CAS  PubMed  Google Scholar 

  40. Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011).

    CAS  PubMed  Google Scholar 

  41. Martinez, J. J., Mulvey, M. A., Schilling, J. D., Pinkner, J. S. & Hultgren, S. J. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J. 19, 2803–2812 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Schilling, J. D., Mulvey, M. A., Vincent, C. D., Lorenz, R. G. & Hultgren, S. J. Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J. Immunol. 166, 1148–1155 (2001).

    CAS  PubMed  Google Scholar 

  43. Bens, M. et al. Flagellin/TLR5 signalling activates renal collecting duct cells and facilitates invasion and cellular translocation of uropathogenic Escherichia coli. Cell. Microbiol. 16, 1503–1517 (2014).

    CAS  PubMed  Google Scholar 

  44. Andersen-Nissen, E. et al. Cutting edge: Tlr5-/- mice are more susceptible to Escherichia coli urinary tract infection. J. Immunol. 178, 4717–4720 (2007).

    CAS  PubMed  Google Scholar 

  45. Zhang, D. et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522–1526 (2004).

    CAS  PubMed  Google Scholar 

  46. Wang, G., Li, X. & Wang, Z. APD2: the updated antimicrobial peptide database and its application in peptide design. Nucleic Acids Res. 37, D933–D937 (2009).

    CAS  PubMed  Google Scholar 

  47. Ganz, T. The role of antimicrobial peptides in innate immunity. Integr. Comp. Biol. 43, 300–304 (2003).

    CAS  PubMed  Google Scholar 

  48. Walch, M. et al. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell 157, 1309–1323 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kudryashova, E. et al. Human defensins facilitate local unfolding of thermodynamically unstable regions of bacterial protein toxins. Immunity 41, 709–721 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Rathinakumar, R., Walkenhorst, W. F. & Wimley, W. C. Broad-spectrum antimicrobial peptides by rational combinatorial design and high-throughput screening: the importance of interfacial activity. J. Am. Chem. Soc. 131, 7609–7617 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Almeida, P. F. & Pokorny, A. Mechanisms of antimicrobial, cytolytic, and cell-penetrating peptides: from kinetics to thermodynamics. Biochemistry 48, 8083–8093 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, H. et al. Contribution of structural domains to the activity of ribonuclease 7 against uropathogenic bacteria. Antimicrob. Agents Chemother. 57, 766–774 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Valore, E. V. et al. Human β-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest. 101, 1633–1642 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Abou Alaiwa, M. H. et al. pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37. Proc. Natl Acad. Sci. USA 111, 18703–18708 (2014).

    CAS  PubMed  Google Scholar 

  55. Schroeder, B. O. et al Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 469, 419–423 (2011).

    CAS  PubMed  Google Scholar 

  56. Guilhelmelli, F. et al. Antibiotic development challenges: the various mechanisms of action of antimicrobial peptides and of bacterial resistance. Front. Microbiol. 4, 353 (2013).

    PubMed  PubMed Central  Google Scholar 

  57. Kai-Larsen, Y. et al. Uropathogenic Escherichia coli modulates immune responses and its curli fimbriae interact with the antimicrobial peptide LL-37. PLoS Pathog. 6, e1001010 (2010).

    PubMed  PubMed Central  Google Scholar 

  58. Yang, D. et al. Defensin participation in innate and adaptive immunity. Curr. Pharm. Des. 13, 3131–3139 (2007).

    CAS  PubMed  Google Scholar 

  59. Neumann, A. et al. The antimicrobial peptide LL-37 facilitates the formation of neutrophil extracellular traps. Biochem. J. 464, 3–11 (2014).

    CAS  PubMed  Google Scholar 

  60. Kruger, P. et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathog. 11, e1004651 (2015).

    PubMed  PubMed Central  Google Scholar 

  61. Chromek, M. et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 12, 636–641 (2006).

    CAS  PubMed  Google Scholar 

  62. Nielsen, K. L. et al. Role of urinary cathelicidin LL-37 and human β-defensin 1 in uncomplicated Escherichia coli urinary tract infections. Infect. Immun. 82, 1572–1578 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Chromek, M. The role of the antimicrobial peptide cathelicidin in renal diseases. Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467-014-2895-3.

  64. Danka, E. S. & Hunstad, D. A. Cathelicidin augments epithelial receptivity and pathogenesis in experimental Escherichia coli cystitis. J. Infect. Dis. 211, 1164–1173 (2015).

    CAS  PubMed  Google Scholar 

  65. Oottamasathien, S. et al. A murine model of inflammatory bladder disease: cathelicidin peptide induced bladder inflammation and treatment with sulfated polysaccharides. J. Urol. 186, 1684–1692 (2011).

    CAS  PubMed  Google Scholar 

  66. Johansson, J., Gudmundsson, G. H., Rottenberg, M. E., Berndt, K. D. & Agerberth, B. Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J. Biol. Chem. 273, 3718–3724 (1998).

    CAS  PubMed  Google Scholar 

  67. Lehrer, R. I., Lichtenstein, A. K. & Ganz, T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu. Rev. Immunol. 11, 105–128 (1993).

    CAS  PubMed  Google Scholar 

  68. Liu, L., Zhao, C., Heng, H. H. & Ganz, T. The human β-defensin-1 and α-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry. Genomics 43, 316–320 (1997).

    CAS  PubMed  Google Scholar 

  69. Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3, 710–720 (2003).

    CAS  PubMed  Google Scholar 

  70. Ihi, T., Nakazato, M., Mukae, H. & Matsukura, S. Elevated concentrations of human neutrophil peptides in plasma, blood, and body fluids from patients with infections. Clin. Infect. Dis. 25, 1134–1140 (1997).

    CAS  PubMed  Google Scholar 

  71. Tikhonov, I., Rebenok, A. & Chyzh, A. A study of interleukin-8 and defensins in urine and plasma of patients with pyelonephritis and glomerulonephritis. Nephrol. Dial. Transplant. 12, 2557–2561 (1997).

    CAS  PubMed  Google Scholar 

  72. Porter, E. et al. Distinct defensin profiles in Neisseria gonorrhoeae and Chlamydia trachomatis urethritis reveal novel epithelial cell-neutrophil interactions. Infect. Immun. 73, 4823–4833 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Quayle, A. J. et al. Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract. Am. J. Pathol. 152, 1247–1258 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, A. P. et al. Antibacterial activity and mechanism of recombinant human α defensin 5 against clinical antibiotic-resistant strains. African J. Microbiol. Res. 4, 626–633 (2010).

    Google Scholar 

  75. Spencer, J. D. et al. Human α defensin 5 expression in the human kidney and urinary tract. PLoS ONE 7, e31712 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Porter, E. M. et al. Isolation of human intestinal defensins from ileal neobladder urine. FEBS Lett. 434, 272–276 (1998).

    CAS  PubMed  Google Scholar 

  77. Townes, C. L., Ali, A., Robson, W., Pickard, R. & Hall, J. Tolerance of bacteriuria after urinary diversion is linked to antimicrobial peptide activity. Urology 77, 509.e1–509.e8 (2011).

    Google Scholar 

  78. Schutte, B. C. et al. Discovery of five conserved β-defensin gene clusters using a computational search strategy. Proc. Natl Acad. Sci. USA 99, 2129–2133 (2002).

    CAS  PubMed  Google Scholar 

  79. Lehmann, J. et al. Expression of human β-defensins 1 and 2 in kidneys with chronic bacterial infection. BMC Infect. Dis. 2, 20 (2002).

    PubMed  PubMed Central  Google Scholar 

  80. Zucht, H. D. et al. Human β-defensin-1: a urinary peptide present in variant molecular forms and its putative functional implication. Eur. J. Med. Res. 3, 315–323 (1998).

    CAS  PubMed  Google Scholar 

  81. Hiratsuka, T. et al. Structural analysis of human β-defensin-1 and its significance in urinary tract infection. Nephron 85, 34–40 (2000).

    CAS  PubMed  Google Scholar 

  82. Nienhouse, V. et al. Interplay between bladder microbiota and urinary antimicrobial peptides: mechanisms for human urinary tract infection risk and symptom severity. PLoS ONE 9, e114185 (2014).

    PubMed  PubMed Central  Google Scholar 

  83. Kraemer, B. F. et al. Novel anti-bacterial activities of β-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog. 7, e1002355 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kandaswamy, K. et al. Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis. Proc. Natl Acad. Sci. USA 110, 20230–20235 (2013).

    CAS  PubMed  Google Scholar 

  85. Rohrl, J., Yang, D., Oppenheim, J. J. & Hehlgans, T. Human β-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2. J. Immunol. 184, 6688–6694 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhao, J., Wang, Z., Chen, X., Wang, J. & Li, J. Effects of intravesical liposome-mediated human β-defensin-2 gene transfection in a mouse urinary tract infection model. Microbiol. Immunol. 55, 217–223 (2011).

    CAS  PubMed  Google Scholar 

  87. Huttner, K. M., Kozak, C. A. & Bevins, C. L. The mouse genome encodes a single homolog of the antimicrobial peptide human β-defensin 1. FEBS Lett. 413, 45–49 (1997).

    CAS  PubMed  Google Scholar 

  88. Bals, R., Goldman, M. J. & Wilson, J. M. Mouse β-defensin 1 is a salt-sensitive antimicrobial peptide present in epithelia of the lung and urogenital tract. Infect. Immun. 66, 1225–1232 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Morrison, G. M. et al. Mouse β defensin-1 is a functional homolog of human β defensin-1. Mamm. Genome 9, 453–457 (1998).

    CAS  PubMed  Google Scholar 

  90. Becknell, B. et al. Expression and antimicrobial function of β-defensin 1 in the lower urinary tract. PLoS ONE 8, e77714 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Morrison, G., Kilanowski, F., Davidson, D. & Dorin, J. Characterization of the mouse β defensin 1, Defb1, mutant mouse model. Infect. Immun. 70, 3053–3060 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Biragyn, A. et al. Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2. Science 298, 1025–1029 (2002).

    CAS  PubMed  Google Scholar 

  93. Zhou, Y. S. et al. Partial deletion of chromosome 8 β-defensin cluster confers sperm dysfunction and infertility in male mice. PLoS Genet. 9, e1003826 (2013).

    PubMed  PubMed Central  Google Scholar 

  94. Navid, F. et al. Induction of regulatory T cells by a murine β-defensin. J. Immunol. 188, 735–743 (2012).

    CAS  PubMed  Google Scholar 

  95. Rosenberg, H. F. RNase A ribonucleases and host defense: an evolving story. J. Leukoc. Biol. 83, 1079–1087 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Simanski, M., Dressel, S., Glaser, R. & Harder, J. RNase 7 protects healthy skin from Staphylococcus aureus colonization. J. Invest. Dermatol. 130, 2836–2838 (2010).

    CAS  PubMed  Google Scholar 

  97. Becknell, B. et al. Ribonucleases 6 and 7 have antimicrobial function in the human and murine urinary tract. Kidney Int. 87, 151–161 (2014).

    PubMed  PubMed Central  Google Scholar 

  98. Spencer, J. D. et al. Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. Kidney Int. 80, 174–180 (2011).

    CAS  PubMed  Google Scholar 

  99. Spencer, J. D. et al. Ribonuclease 7, an antimicrobial peptide upregulated during infection, contributes to microbial defense of the human urinary tract. Kidney Int. 83, 615–625. (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Boix, E. & Nogues, M. V. Mammalian antimicrobial proteins and peptides: overview on the RNase A superfamily members involved in innate host defence. Mol. Biosyst. 3, 317–335 (2007).

    CAS  PubMed  Google Scholar 

  101. Huang, Y. C. et al. The flexible and clustered lysine residues of human ribonuclease 7 are critical for membrane permeability and antimicrobial activity. J. Biol. Chem. 282, 4626–4633 (2007).

    CAS  PubMed  Google Scholar 

  102. Harder, J. & Schroder, J. M. RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J. Biol. Chem. 277, 46779–46784 (2002).

    CAS  PubMed  Google Scholar 

  103. Wang, H. et al. Contribution of structural domains to ribonuclease 7's activity against uropathogenic bacteria. Antimicrob. Agents Chemother. 57, 766–774 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Spencer, J. D. et al. An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract. Kidney Int. 85, 1179–1191 (2013).

    PubMed  PubMed Central  Google Scholar 

  105. Abtin, A. et al. Degradation by stratum corneum proteases prevents endogenous RNase inhibitor from blocking antimicrobial activities of RNase 5 and RNase 7. J. Invest. Dermatol. 129, 2193–2201 (2009).

    CAS  PubMed  Google Scholar 

  106. Blazquez, M., Fominaya, J. M. & Hofsteenge, J. Oxidation of sulfhydryl groups of ribonuclease inhibitor in epithelial cells is sufficient for its intracellular degradation. J. Biol. Chem. 271, 18638–18642 (1996).

    CAS  PubMed  Google Scholar 

  107. Zasloff, M. The antibacterial shield of the human urinary tract. Kidney Int. 83, 548–550 (2013).

    CAS  PubMed  Google Scholar 

  108. Hagan, E. C., Lloyd, A. L., Rasko, D. A., Faerber, G. J. & Mobley, H. L. Escherichia coli global gene expression in urine from women with urinary tract infection. PLoS Pathog. 6, e1001187 (2010).

    PubMed  PubMed Central  Google Scholar 

  109. Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004).

    CAS  PubMed  Google Scholar 

  110. Park, C. H., Valore, E. V., Waring, A. J. & Ganz, T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276, 7806–7810 (2001).

    CAS  PubMed  Google Scholar 

  111. Moulouel, B. et al. Hepcidin regulates intrarenal iron handling at the distal nephron. Kidney Int. 84, 756–766 (2013).

    CAS  PubMed  Google Scholar 

  112. Bellamy, W., Takase, M., Wakabayashi, H., Kawase, K. & Tomita, M. Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. J. Appl. Bacteriol. 73, 472–479 (1992).

    CAS  PubMed  Google Scholar 

  113. Abrink, M., Larsson, E., Gobl, A. & Hellman, L. Expression of lactoferrin in the kidney: implications for innate immunity and iron metabolism. Kidney Int. 57, 2004–2010 (2000).

    CAS  PubMed  Google Scholar 

  114. Paragas, N. et al. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat. Med. 17, 216–222 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Berger, T. et al. Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc. Natl Acad. Sci. USA 103, 1834–1839 (2006).

    CAS  PubMed  Google Scholar 

  116. Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).

    CAS  PubMed  Google Scholar 

  117. Holmes, M. A., Paulsene, W., Jide, X., Ratledge, C. & Strong, R. K. Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure 13, 29–41 (2005).

    CAS  PubMed  Google Scholar 

  118. Steigedal, M. et al. Lipocalin 2 imparts selective pressure on bacterial growth in the bladder and is elevated in women with urinary tract infection. J. Immunol. 193, 6081–6089 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Corbin, B. D. et al. Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319, 962–965 (2008).

    CAS  PubMed  Google Scholar 

  120. van Zoelen, M. A. et al. Expression and role of myeloid-related protein-14 in clinical and experimental sepsis. Am. J. Respir. Crit. Care Med. 180, 1098–1106 (2009).

    CAS  PubMed  Google Scholar 

  121. Dessing, M. C. et al. S100A8/A9 is not involved in host defense against murine urinary tract infection. PLoS ONE 5, e13394 (2010).

    PubMed  PubMed Central  Google Scholar 

  122. Jaillon, S. et al. The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection. Immunity 40, 621–632 (2014).

    CAS  PubMed  Google Scholar 

  123. Mayrer, A. R., Miniter, P. & Andriole, V. T. Immunopathogenesis of chronic pyelonephritis. Am. J. Med. 75, 59–70 (1983).

    CAS  PubMed  Google Scholar 

  124. Kokot, F. & Dulawa, J. Tamm-Horsfall protein updated. Nephron 85, 97–102 (2000).

    CAS  PubMed  Google Scholar 

  125. Darisipudi, M. N. et al. Uromodulin triggers IL-1β-dependent innate immunity via the NLRP3 inflammasome. J. Am. Soc. Nephrol. 23, 1783–1789 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Muchmore, A. V. & Decker, J. M. Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women. Science 229, 479–481 (1985).

    CAS  PubMed  Google Scholar 

  127. Hawthorn, L. A., Bruce, A. W. & Reid, G. Ability of uropathogens to bind to Tamm Horsfall protein-coated renal tubular cells. Urol. Res. 19, 301–304 (1991).

    CAS  PubMed  Google Scholar 

  128. Bates, J. M. et al. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int. 65, 791–797 (2004).

    CAS  PubMed  Google Scholar 

  129. Pak, J., Pu, Y., Zhang, Z. T., Hasty, D. L. & Wu, X. R. Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J. Biol. Chem. 276, 9924–9930 (2001).

    CAS  PubMed  Google Scholar 

  130. Saemann, M. D. et al. Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J. Clin. Invest. 115, 468–475 (2005).

    PubMed  PubMed Central  Google Scholar 

  131. Peschel, A. & Sahl, H. G. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat. Rev. Microbiol. 4, 529–536 (2006).

    CAS  PubMed  Google Scholar 

  132. Haversen, L. A. et al. Human lactoferrin and peptides derived from a surface-exposed helical region reduce experimental Escherichia coli urinary tract infection in mice. Infect. Immun. 68, 5816–5823 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Hertting, O. et al. Vitamin D induction of the human antimicrobial Peptide cathelicidin in the urinary bladder. PLoS ONE 5, e15580 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Luthje, P. et al. Estrogen supports urothelial defense mechanisms. Sci. Transl. Med. 5, 190ra80 (2013).

    PubMed  Google Scholar 

  135. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 103, 843–852 (1999).

  136. Wolfe, A. J. et al. Evidence of uncultivated bacteria in the adult female bladder. J. Clin. Microbiol. 50, 1376–1383 (2012).

    PubMed  PubMed Central  Google Scholar 

  137. Chen, Q. X. et al. Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population. Genes Immun. 8, 439–443 (2007).

    CAS  PubMed  Google Scholar 

  138. Hardwick, R. J. et al. β-defensin genomic copy number is associated with HIV load and immune reconstitution in sub-saharan Africans. J. Infect. Dis. 206, 1012–1019 (2012).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

J.D.S.'s work is supported by an NIH Grant (NIDDK) K08 DK094970. B.B.'s work is supported by an NIH Grant (NIDDK) K08 DK102594.01A1.

Author information

Authors and Affiliations

  1. Division of Pediatric Nephrology, The Research Institute at Nationwide Children's Hospital, Center for Clinical and Translational Research, 700 Children's Drive, Columbus, 43205, OH, USA

    Brian Becknell, Andrew Schwaderer & John David Spencer

  2. Division of Pediatric Nephrology, Children's Foundation Research Institute at Le Bonheur Children's Hospital, 848 Adams Avenue, Memphis, 38103, TN, USA

    David S. Hains

Authors
  1. Brian Becknell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew Schwaderer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David S. Hains
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John David Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.D.S. and B.B. researched data for the article and provided substantial contributions to discussions of its content. All authors wrote the article and reviewed/edited the manuscript before submission.

Corresponding authors

Correspondence to Brian Becknell or John David Spencer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Becknell, B., Schwaderer, A., Hains, D. et al. Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis. Nat Rev Nephrol 11, 642–655 (2015). https://doi.org/10.1038/nrneph.2015.105

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2015.105

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing