title: Severe Nephrotoxic Nephritis following Conditional and Kidney-Specific Knockdown of Stanniocalcin-1.
abstract: BACKGROUND
  Inflammation is the hallmark of nephrotoxic nephritis. Stanniocalcin-1 (STC1), a pro-survival factor, inhibits macrophages, stabilizes endothelial barrier function, and diminishes trans-endothelial migration of leukocytes; consistently, transgenic (Tg) overexpression of STC1 protects from nephrotoxic nephritis. Herein, we sought to determine the phenotype of nephrotoxic nephritis after conditional and kidney-specific knockdown of STC1.
  
  
  METHODS
  We used Tg mice that, express either STC1 shRNA (70% knockdown of STC1 within 4d) or scrambled shRNA (control) upon delivery of Cre-expressing plasmid to the kidney using ultrasound microbubble technique. Sheep anti-mouse GBM antibody was administered 4d after shRNA activation; and mice were euthanized 10 days later for analysis.
  
  
  RESULTS
  Serum creatinine, proteinuria, albuminuria and urine output were similar 10 days after anti-GBM delivery in both groups; however, anti-GBM antibody delivery to mice with kidney-specific knockdown of STC1 produced severe nephrotoxic nephritis, characterized by severe tubular necrosis, glomerular hyalinosis/necrosis and massive cast formation, while control mice manifested mild tubular injury and crescentic glomerulonephritis. Surprisingly, the expression of cytokines/chemokines and infiltration with T-cells and macrophages were also diminished in STC1 knockdown kidneys. Staining for sheep anti-mouse GBM antibody, deposition of mouse C3 and IgG in the kidney, and antibody response to sheep IgG were equal.
  
  
  CONCLUSIONS
  nephrotoxic nephritis after kidney-specific knockdown of STC1 is characterized by severe tubular and glomerular necrosis, possibly due to loss of STC1-mediated pro-survival factors, and we attribute the paucity of inflammation to diminished release of cytokines/chemokines/growth factors from the necrotic epithelium.
authors.affiliation: Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Luping
authors.initials: L
authors.lastname: Huang
authors.affiliation: Dental Branch, University of Texas Health Science Center, Houston, TX, United States of America.
authors.forename: Yahuan
authors.initials: Y
authors.lastname: Lou
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 25009, Jiangsu, P. R.China.
authors.forename: Huiming
authors.initials: H
authors.lastname: Ju
authors.affiliation: Center of General Surgery, Chengdu General Hospital of Chengdu Military Area Command, Chengdu, P. R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Jenny Szu-Chin
authors.initials: JS
authors.lastname: Pan
authors.affiliation: Dental Branch, University of Texas Health Science Center, Houston, TX, United States of America.
authors.forename: April
authors.initials: A
authors.lastname: Ross
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Pathology and Laboratory Medicine, Methodist Hospital/Weill Cornell Medical College, Houston, Texas, United States of America.
authors.forename: Luan D
authors.initials: LD
authors.lastname: Truong
authors.affiliation: Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Sheikh-Hamad
mesh_terms: D000199:Actins / Q000378:metabolism; D000418:Albumins / Q000032:analysis; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D002460:Cell Line; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity; D007074:Immunoglobulin G / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009393:Nephritis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: D000199:Actins; D000418:Albumins; D000906:Antibodies; D016207:Cytokines; D006023:Glycoproteins; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; C051795:teleocalcin; D003404:Creatinine; D006861:Hydrogen Peroxide