Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1.

Abstract

Endotoxin-related acute kidney injury has been shown to profoundly induce nitric oxide (NO), which activates sympathetic and renin-angiotensin system, resulting in renal vasoconstriction. While vascular muscle cells are known to upregulate inducible NO synthase (iNOS), less is known about the endothelium as a source of NO during endotoxemia. Studies were, therefore, undertaken both in vitro in mouse microvascular endothelial cells and in vivo in transgenic mice with overexpression of endothelial GTP cyclohydrolase, the rate-limiting enzyme for tetrahydrobiopterin, a cofactor for NO synthase. LPS significantly induced endothelial cell iNOS expression and NO concentration in the culture media, with no change in endothelial NO synthase expression. GTP cyclohydrolase-1 transgenic (Tg) mice demonstrated a significant increase in baseline urine NO-to-creatinine ratio and a more significant increase in renal iNOS expression and serum NO levels with LPS treatment compared with the wild-type (WT) mice. Glomerular filtration rate and renal blood flow decreased significantly in Tg mice with 1.0 mg/kg LPS, while no changes were observed in WT with the same dose of LPS. Serum IL-6 levels were significantly higher in Tg compared with WT mice during endotoxemia. The antioxidant tempol improved the glomerular filtration rate in the Tg mice. Thus endothelium can be an important source of iNOS and serum NO concentration during endotoxemia, thereby increasing the sensitivity to AKI. Reactive oxygen species appear to be involved in this acute renal injury in Tg mice during endotoxemia.

DOI: 10.1152/ajprenal.00538.2007

5 Figures and Tables

Cite this paper

@article{Wang2008EndotoxemiarelatedAK, title={Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1.}, author={Wei Wang and Einath Zolty and Sandor A. Falk and Sandra N. Summer and Zhu Zhou and Patricia E Gengaro and Sarah G Faubel and Nicholas J. Alp and Keith M. Channon and Robert Schrier}, journal={American journal of physiology. Renal physiology}, year={2008}, volume={294 3}, pages={F571-6} }