Reactive oxygen species (ROS), endothelial injury and macrophages play critical roles in ischemia/reperfusion (I/R) kidney injury. Our data show stanniocalcin-1 (STC1) diminishes superoxide generation in macrophages, through induction of uncoupling protein-2 (UCP2), decreases the response of macrophages to chemoattractants- and migration across an endothelial monolayer. In cultured endothelial cells, STC1 preserve barrier function. STC1: diminishes superoxide generation;inhibits cytokine-induced activation of Jun-N- terminal kinase (JNK) and loss of tight junction proteins expression. STC1 transgenic mice, which exhibit elevated serum levels and preferential expression of STC1 in macrophages and endothelium, display resistance to I/R kidney injury. Overall hypothesis: STC1 protects from I/R kidney injury through: suppression of superoxide generation;maintenance of normal endothelial barrier function following I/R kidney injury;and inhibition of macrophages. In Objective I, we will determine the role of superoxide and Daxx in STC1-mediated inhibition of JNK in endothelial cells. In Objective II, we will determine the effect of STC1 on hypoxia/reoxygenation (H/RO)-induced changes in the expression and assembly of tight junction proteins in cultured primary kidney endothelial cells. In the context of I/R kidney injury, Objective III will examine endothelial leakage to macromolecules, kidney inflammation and function after kidney endothelium-specific or macrophage-specific overexpression or deletion of STC1. Few therapeutic options are currently available for acute kidney injury (AKI). Our data identify STC1 as a potential therapeutic target for ischemic injury in the kidney and other organs, and our proposed studies will further elucidate STC1 mechanisms of action.

Public Health Relevance

The development of kidney failure is associated with high rate of complications and death, and the options for treatment are limited. Our results show that mice engineered to produce large amounts of stanniocalcin-1 protein are resistant to insults that normally cause kidney failure. We plan to study how stanniocalcin-1 protects from kidney failure, and our proposed experiments could lead to new therapies for this costly disease.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002006-01A1
Application #
8633244
Study Section
Nephrology (NEPH)
Project Start
2014-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Michael E Debakey VA Medical Center
Department
Type
DUNS #
078446044
City
Houston
State
TX
Country
United States
Zip Code
77030
Lin, Ligen; Lee, Jong Han; Buras, Eric D et al. (2016) Ghrelin receptor regulates adipose tissue inflammation in aging. Aging (Albany NY) 8:178-91
Pan, Jenny Szu-Chin; Huang, Luping; Belousova, Tatiana et al. (2015) Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway. J Am Soc Nephrol 26:364-78
Scherzer, Pnina; Gal-Moscovici, Anca; Sheikh-Hamad, David et al. (2015) Sodium-pump gene-expression, protein abundance and enzyme activity in isolated nephron segments of the aging rat kidney. Physiol Rep 3:
Huang, Luping; Zhang, Lin; Ju, Huiming et al. (2015) Stanniocalcin-1 inhibits thrombin-induced signaling and protects from bleomycin-induced lung injury. Sci Rep 5:18117
Pan, Jenny Szu-Chin; Sheikh-Hamad, David (2015) Remote ischemic preconditioning for kidney protection. JAMA 313:2124-5
Pan, Jenny Szu-Chin; Sheikh-Hamad, David (2015) Remote Ischemic Preconditioning and Postoperative Renal Dysfunction--Reply. JAMA 314:1520
Huang, Luping; Lou, Yahuan; Ju, Huiming et al. (2015) Severe Nephrotoxic Nephritis following Conditional and Kidney-Specific Knockdown of Stanniocalcin-1. PLoS One 10:e0138440
Lin, Ligen; Lee, Jong Han; Bongmba, Odelia Y N et al. (2014) The suppression of ghrelin signaling mitigates age?associated thermogenic impairment. Aging (Albany NY) 6:1019-32
Huang, Luping; Belousova, Tatiana; Pan, Jenny Szu-Chin et al. (2014) AKI after conditional and kidney-specific knockdown of stanniocalcin-1. J Am Soc Nephrol 25:2303-15