ET‐1 increases reactive oxygen species following hypoxia and high‐salt diet in the mouse glomerulus

Abstract

Aim The current study was designed to determine whether ET-1 derived from endothelial cells contributes to oxidative stress in the glomerulus of mice subjected to a high salt diet and/or hypoxia. Methods C57BL6/J control mice or vascular endothelial cell ET-1 knockout (VEET KO) mice were subjected to three-hour exposure to hypoxia (8% O2) and or 2 weeks of high salt diet (4% NaCl) prior to metabolic cage assessment of renal function and isolation of glomeruli for determination of reactive oxygen species (ROS). Results In control mice, hypoxia significantly increased urinary protein excretion during the initial 24 hrs, but only in animals on a high salt diet. Hypoxia increased glomerular ET-1 mRNA expression in control, but not in vascular endothelial cell ET-1 knockout (VEET KO) mice. Under normoxic conditions, mice on a high salt diet had approximately 150% higher glomerular ET-1 mRNA expression compared to a normal salt diet (p<0.05). High salt diet administration significantly increased glomerular ROS production in flox control, but not in glomeruli isolated from VEET KO mice. In C57BL6/J mice, the ETA receptor selective antagonist, ABT-627, significantly attenuated the increase in glomerular ROS production produced by high salt diet. In addition, chronic infusion of C57BL6/J mice with a sub-pressor dose of ET-1 (osmotic pumps) significantly increased levels of glomerular ROS that were prevented by ETA antagonist treatment. Conclusion These data suggest that both hypoxia and a high salt diet increases glomerular ROS production via endothelial derived ET-1-ETA receptor activation and provide a potential mechanism for ET-1 induced nephropathy.

Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery

“…Circulating levels of ET-1 are elevated in diabetes [28], which may be due to either increased ET-1 production or reduced clearance. Furthermore, it was recently demonstrated that ET-1, via ETA-Rs, increases the glomerular production of reactive oxygen species and urinary protein leakage during exposure to hypoxia in mice fed a highsalt diet [29]. Thus, ET-1 signalling via ETA-Rs may play an important role in the development of diabetic nephropathy, especially considering the intrarenal hypoxia that develops soon after the onset of diabetes [30].…”

Simiao pill ameliorates renal glomerular injury via increasing Sirt1 expression and suppressing NF-κB/NLRP3 inflammasome activation in high fructose-fed rats

“…The glomeruli were isolated from rat kidney cortex as described (Heimlich et al, 2014). Glomeruli were homogenized in a Dounce homogenizer in RIPA buffer (consisting of 0.1% sodium dodecyl sulfate, 1% NP-40, 150 mM NaCl, 1% sodium deoxycholate and 10 mM ethylenediaminetetraacetic acid in 25 mM Tris-HCl (pH 7.2) and then centrifuged ( 12,000g, 4°C) for 20 min.…”

Endothelium-derived ET-1 and the development of renal injury

“…To (38), and stimulates glomerular formation of reactive oxygen species in response to highsalt diet or hypoxia (15).…”