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Title: Severe nephrotoxic nephritis following conditional and kidney-specific knockdown of stanniocalcin-1

Author
item HUANG, LUPING - Baylor College Of Medicine
item LOU, YAHUAN - University Of Texas Health Science Center
item JU, HULMING - Yangzhou University
item ZHANG, LIN - Chengdu Institute
item PAN, JENNY SZY-CHIN - Baylor College Of Medicine
item ROSS, APRIL - University Of Texas Health Science Center
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)
item TRUONG, LUAN - Weill Medical College - Cornell
item SHEIKH-HAMAD, DAVID - Weill Medical College - Cornell

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2015
Publication Date: 9/22/2015
Citation: Huang, L., Lou, Y., Ju, H., Zhang, L., Pan, J., Ross, A., Sun, Y., Truong, L.D., Sheikh-Hamad, D. 2015. Severe nephrotoxic nephritis following conditional and kidney-specific knockdown of stanniocalcin-1. PLoS One.10:e0138440.

Interpretive Summary: The hallmark feature of nephrotoxic nephritis is inflammation. Stanniocalcin-1 (STC1) is a pro-survival factor, which inhibits macrophages, stabilizes endothelial barrier, and diminishes leukocyte migration. Herein, we sought to determine the characteristics of nephrotoxic nephritis after kidney-specific deletion of STC1. We found that kidney-specific deletion of STC1 show severe tubular and glomerular necrosis. This new finding suggests that STC1 is involved in the development of nephrotoxic nephritis.

Technical Abstract: 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. 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. 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. 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.