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2015 ; 10
(9
): e0138440
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Severe Nephrotoxic Nephritis following Conditional and Kidney-Specific Knockdown
of Stanniocalcin-1
#MMPMID26393521
Huang L
; Lou Y
; Ju H
; Zhang L
; Pan JS
; Ross A
; Sun Y
; Truong LD
; Sheikh-Hamad D
PLoS One
2015[]; 10
(9
): e0138440
PMID26393521
show ga
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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