Key result
Kidney-specific knockdown of STC1 during nephrotoxic nephritis in mice caused severe tubular and glomerular necrosis with massive cast formation, while surprisingly reducing inflammatory cell infiltration and cytokine expression.
Why the study?
Does kidney-specific knockdown of STC1 alter the phenotype of nephrotoxic nephritis in mice?
Does kidney-specific knockdown of STC1 alter the phenotype of nephrotoxic nephritis in mice?
Kidney-specific knockdown of STC1 exacerbates tubular and glomerular necrosis in nephrotoxic nephritis while paradoxically reducing inflammation, suggesting STC1 is a critical pro-survival factor for tubular epithelium.
STC1 knockdown may worsen necrosis despite curbing inflammation in murine nephritis; leaves open net benefit and clinical translation.
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.
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Huang et al. (2015) studied Nephrotoxic nephritis. Kidney-specific knockdown of STC1 (STC1 shRNA) vs. Scrambled shRNA (control) was evaluated on Phenotype of nephrotoxic nephritis (glomerular hyalinosis/necrosis, tubular casts, and inflammation). Kidney-specific knockdown of STC1 during nephrotoxic nephritis in mice caused severe tubular and glomerular necrosis with massive cast formation, while surprisingly reducing inflammatory cell infiltration and cytokine expression.
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