Abstract P016: Sex Differential Effects Of Hyperoxia And Thioredoxin Reductase-1 Inhibition On The Kidney Endothelin-1 System

Abstract

The vasoactive peptide endothelin-1 (ET-1) is critical in lung and kidney injury. Notably, renal damageand hyperoxia-induced lung disease are more prevalent in males than females. Aurothioglucose (ATG),an inhibitor of thioredoxin reductase-1, attenuates hyperoxia-induced lung injury in mice; however, theeffects of hyperoxia and/or ATG treatment on the kidney ET-1 system remain unknown. Wehypothesized that hyperoxia would activate the renal ET-1 system and that ATG treatment wouldattenuate this activation. Male and female adult C57Bl/6 mice received a single injection of saline orATG (25mg/Kg, i.p.) and were exposed to room air (RA) or >90% O2 for 72 hours. Kidney and spleen werecollected for assessment of the ET-1 system by RT-PCR and glomerular morphology and immune cellinfiltration were evaluated by histology and immunohistochemistry, respectively. In male mice,hyperoxia reduced the cortical expression of ET-1 (RA vs. hyperoxia: 1 ± 0.05 vs. 0.34 ± 0.04, p<0.05;n=3-4/group) and ameliorated the expression of ETA receptor. In RA males, treatment with ATGsignificantly halved the expression of ET-1 and ETB receptor (saline vs. ATG, ET-1: 1 ± 0.05 vs. 0.45 ± 0.07,p<0.05; n=3-4/group; ETB receptor: 1 ± 0.09 vs. 0.37 ± 0.10, p<0.05; n=3-4/group), but had no effect inhyperoxic males. Contrarily, hyperoxic females demonstrated a 3-fold upregulation of corticalETB receptor expression, which was significantly prevented by ATG (saline vs. ATG: 2.80 ± 0.37 vs. 0.95 ±0.27, p<0.05; n=3-4/group). ATG treatment in hyperoxic females also decreased the cortical expressionof ET-1 and ETA receptor. No changes in cortical inflammation or glomerular morphology were observed.Further preliminary results showed that hyperoxia led to a 4-fold increase in splenic ET-1 expression insaline-treated mice, and a 7-fold increase in mice treated with ATG. These results demonstrate sexdifferences in the effects of hyperoxia and ATG treatment in the renal ET-1 system and highlight ATG asa possible therapeutic target to attenuate hyperoxia-induced kidney damage. Funded by NIHK01HL145324 and UAB Diabetes Research Center Pilot Project grant to CDM.