Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis

Xinli Shao, Ru Yang Mei Yan, Yajuan Li, Yong Du, Indu Raman, Bo Zhang, Ward Wakeland, Peter Igarashi, Chandra Mohan, Quan Zhen Li

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Objective To ascertain whether engineered expression of kallikreins within the kidneys, using an inducible Cre/loxP system, can ameliorate murine lupus nephritis. Methods In mice with a lupus-prone genetic background, we engineered the expression of tamoxifen-inducible Cre recombinase under the control of a kidney-specific promoter whose activation initiates murine kallikrein-1 expression within the kidneys. These transgenic mice were injected with either tamoxifen or vehicle at age 2 months and then were monitored for 8 months for kallikrein expression and disease. Results Elevated expression of kallikrein was detected in the kidney and urine of tamoxifen-injected mice but not in controls. At age 10 months, all vehicle-injected mice developed severe lupus nephritis, as evidenced by increased proteinuria (mean ± SD 13.43 ± 5.65 mg/24 hours), increased blood urea nitrogen (BUN) and serum creatinine levels (39.86 ± 13.45 mg/dl and 15.23 ± 6.89 mg/dl, respectively), and severe renal pathology. In contrast, the tamoxifen-injected mice showed significantly reduced proteinuria (6.6 ± 4.12 mg/24 hours), decreased BUN and serum creatinine levels (15.71 ± 8.17 mg/dl and 6.64 ± 3.39 mg/dl, respectively), and milder renal pathology. Tamoxifen-induced up-regulation of renal kallikrein expression increased nitric oxide production and dampened renal superoxide production and inflammatory cell infiltration, alluding to some of the pathways through which kallikreins may be operating within the kidneys. Conclusion Local expression of kallikreins within the kidney has the capacity to dampen lupus nephritis, possibly by modulating inflammation and oxidative stress.

Original languageEnglish (US)
Pages (from-to)780-791
Number of pages12
JournalArthritis and rheumatism
Volume65
Issue number3
DOIs
StatePublished - Mar 1 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Shao, X., Yan, R. Y. M., Li, Y., Du, Y., Raman, I., Zhang, B., Wakeland, W., Igarashi, P., Mohan, C., & Li, Q. Z. (2013). Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis. Arthritis and rheumatism, 65(3), 780-791. https://doi.org/10.1002/art.37798