title: Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis.
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.
  
  
  CONCLUSIONS
  Local expression of kallikreins within the kidney has the capacity to dampen lupus nephritis, possibly by modulating inflammation and oxidative stress.
authors.affiliation: University of Texas-Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Shao
authors.forename: Ru
authors.initials: R
authors.lastname: Yang
authors.forename: Mei
authors.initials: M
authors.lastname: Yan
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.forename: Indu
authors.initials: I
authors.lastname: Raman
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: Ward
authors.initials: W
authors.lastname: Wakeland
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
mesh_terms: D000818:Animals; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D019426:Integrases / Q000235:genetics; D007684:Kidney Tubules / Q000166:cytology / Q000502:physiology*; D007763:Lac Operon / Q000235:genetics; D008181:Lupus Nephritis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D020845:Selective Estrogen Receptor Modulators / Q000633:toxicity; D013481:Superoxides / Q000378:metabolism; D013629:Tamoxifen / Q000633:toxicity; D020840:Tissue Kallikreins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020845:Selective Estrogen Receptor Modulators; C485184:enhanced green fluorescent protein; D013629:Tamoxifen; D013481:Superoxides; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; C045073:Cre recombinase; D019426:Integrases; D020840:Tissue Kallikreins