Severe Nephrotoxic Nephritis following Conditional and Kidney-Specific Knockdown of Stanniocalcin-1

Abstract

BackgroundInflammation 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.MethodsWe 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.ResultsSerum 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.Conclusionsnephrotoxic 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.

Transgene expression of Stanniocalcin-1 provides sustained intraocular pressure reduction by increasing outflow facility

“…STC-1 functions as a stress-response protein being produced at relatively low levels during periods of physiologic homeostasis, but upregulated in times of cellular stress [ 29 ] including inflammation [ 30 ], oxidation [ 31 ], and hypoxia [ 32 – 34 ]. This observation is highlighted by STC-1 knockout mice demonstrating a normal phenotype [ 35 ] but develop worse disease compared to controls when subjected to pathologic stress [ 29 , 36 , 37 ]. Our laboratory became interested in STC-1 as a potential IOP-lowering molecule while studying the response of cells involved in aqueous humor drainage following treatment with PGF2α analogue latanoprost free acid (LFA) [ 38 ].…”

Long-term photoreceptor rescue in two rodent models of retinitis pigmentosa by adeno-associated virus delivery of Stanniocalcin-1

“…Stanniocalcin-1 (STC-1) is a unique multifunctional protein that is cellular protective in a variety of tissues including intestine (Wu et al, 2014), heart (Mohammadipoor et al, 2016; Shi et al, 2014; Westberg et al, 2007a), lung (Huang et al, 2015b; Tang et al, 2014), kidney (Huang et al, 2012; Huang et al, 2014; Huang et al, 2015a; Liu et al, 2016; Pan et al, 2015), cerebral neurons (Durukan Tolvanen et al, 2013; Westberg et al, 2007b; Zhang et al, 2000), retinal photoreceptors (Roddy et al, 2012), and retinal ganglion cells (Kim et al, 2013). Cellular protective functions of STC-1 have been attributed to its ability to reduce apoptosis (Huang et al, 2014; Kim et al, 2013; Tang et al, 2014), oxidative stress (Huang et al, 2012; Huang et al, 2015b; Kim et al, 2013; Liu et al, 2016; Nguyen et al, 2009; Roddy et al, 2012; Shi et al, 2014; Tang et al, 2014; Wu et al, 2014), and inflammation (Kanellis et al, 2004; Mohammadipoor et al, 2016; Tang et al, 2014; Wang et al, 2009), which are all pathways involved in RD (Ding et al, 2009).…”