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Title: AKI after conditional and kidney-specific knockdown of Stanniocalcin-1

Author
item HUANG, LUPING - Baylor College Of Medicine
item BELOUSOVA, TATIANA - Baylor College Of Medicine
item SZU-CHIN PAN, JENNY - Baylor College Of Medicine
item DU, JIE - Baylor College Of Medicine
item JU, HUIMING - Baylor College Of Medicine
item LU, LIANGHAO - Baylor College Of Medicine
item ZHANG, PUMIN - Baylor College Of Medicine
item TRUONG, LUAN - Baylor College Of Medicine
item NUOTIO-ANTAR, ALLI - Children'S Nutrition Research Center (CNRC)
item SHEIKH-HAMAD, DAVID - Baylor College Of Medicine

Submitted to: Journal of the American Society of Nephrology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/4/2014
Publication Date: 10/25/2014
Citation: Huang, L., Belousova, T., Szu-Chin Pan, J., Du, J., Ju, H., Lu, L., Zhang, P., Truong, L.D., Nuotio-Antar, A., Sheikh-Hamad, D. 2014. AKI after conditional and kidney-specific knockdown of Stanniocalcin-1. Journal of the American Society of Nephrology. 2(10):2303-2315.

Interpretive Summary: Stanniocalcin-1 (STC1) is a protein that acts in an antioxidant capacity in cells and which is expressed throughout the kidney.However, not much is known about its role in this organ. We generated a novel mouse model which is deficient in STC1 specifically in kidney endothelial cells. These mice displayed a pathological condition that mimics acute kidney injury, due in part to loss of the antioxidant-promoting role of STC1. Increased signs of cell stress and death were observed in STC1-deficient kidney proximal tubule cells. STC1-deficient kidneys also displayed greater infiltration of macrophages, a type of immune cell, suggesting greater inflammatory response. Taken together,these results suggest that STC1 plays an important role in maintaining normal kidney function.

Technical Abstract: Stanniocalcin-1 is an intracrine protein; it binds to the cell surface, is internalized to the mitochondria, and diminishes superoxide generation through induction of uncoupling proteins. In vitro, stanniocalcin-1 inhibits macrophages and preserves endothelial barrier function, and transgenic overexpression of stanniocalcin-1 in mice protects against ischemia-reperfusion kidney injury. We sought to determine the kidney phenotype after kidney endothelium-specific expression of stanniocalcin-1 small hairpin RNA (shRNA). We generated transgenic mice that express stanniocalcin-1 shRNA or scrambled shRNA upon removal of a floxed reporter (phosphoglycerate kinase-driven enhanced green fluorescent protein) and used ultrasound microbubbles to deliver tyrosine kinase receptor-2 promoter-driven Cre to the kidney to permit kidney endothelium-specific shRNA expression. Stanniocalcin-1 mRNA and protein were expressed throughout the kidney in wild-type mice. Delivery of tyrosine kinase receptor-2 promoter-driven Cre to stanniocalcin-1 shRNA transgenic kidneys diminished the expression of stanniocalcin-1 mRNA and protein throughout the kidneys. Stanniocalcin-1 mRNA and protein expression did not change in similarly treated scrambled shRNA transgenic kidneys, and we observed no Cre protein expression in cultured and tyrosine kinase receptor-2 promoter-driven Cre–transfected proximal tubule cells, suggesting that knockdown of stanniocalcin-1 in epithelial cells in vivo may result from stanniocalcin-1 shRNA transfer from endothelial cells to epithelial cells. Kidney-specific knockdown of stanniocalcin-1 led to severe proximal tubule injury characterized by vacuolization, decreased uncoupling of protein-2 expression, greater generation of superoxide, activation of the unfolded protein response, initiation of autophagy, cell apoptosis, and kidney failure. Our observations suggest that stanniocalcin-1 is critical for tubular epithelial survival under physiologic conditions.