ROS dependence of cyclooxygenase-2 induction in rats subjected to unilateral ureteral obstruction

Abstract

Østergaard M, Christensen M, Nilsson L, Carlsen I, Frøkiaer J, Nørregaard R. ROS dependence of cyclooxygenase-2 induction in rats subjected to unilateral ureteral obstruction. Am J Physiol Renal Physiol 306: F259 -F270, 2014. First published November 13, 2013 doi:10.1152/ajprenal.00352.2013.-Oxidative stress resulting from unilateral ureteral obstruction (UUO) may be aggravated by increased production of ROS. Previous studies have demonstrated increased cyclooxygenase (COX)-2 expression in renal medullary interstitial cells (RMICs) in response to UUO. We investigated, both in vivo and in vitro, the role of ROS in the induction of COX-2 in rats subjected to UUO and in RMICs exposed to oxidative and mechanical stress. Rats subjected to 3-day UUO were treated with two mechanistically distinct antioxidants, the NADPH oxidase inhibitor diphenyleneiodonium (DPI) and the complex I inhibitor rotenone (ROT), to interfere with ROS production. We found that UUO-mediated induction of COX-2 in the inner medulla was attenuated by both antioxidants. In addition, DPI and ROT reduced tubular damage and oxidative stress after UUO. Moreover, mechanical stretch induced COX-2 and oxidative stress in RMICs. Likewise, RMICs exposed to H2O2 as an inducer of oxidative stress showed increased COX-2 expression and activity, both of which were reduced by DPI and ROT. Similarly, ROS production, which was increased after exposure of RMICs to H2O2, was also reduced by DPI and ROT. Furthermore, oxidative stress-induced phosphorylation of ERK1/2 and p38 was blocked by both antioxidants, and inhibition of ERK1/2 and p38 attenuated the induction of COX-2 in RMICs. Notably, COX-2 inhibitors further exacerbated the oxidative stress level in H2O2-exposed RMICs. We conclude that oxidative stress as a consequence of UUO stimulates COX-2 expression through the activation of multiple MAPKs and that the induction of COX-2 may exert a cytoprotective function in RMICs. ureteral obstruction; oxidative stress; cyclooxygenase-2; reactive oxygen species OBSTRUCTIVE NEPHROPATHY is an important cause of renal insufficiency in both children and adults. Unilateral ureteral obstruction (UUO) is a well-established experimental rodent model that mimics the severe renal injury found in obstructive nephropathy (19).The hydrostatic pressure increase as a result of obstruction causes massive tubular dilation, interstitial inflammatory infiltration, apoptotic tubular cell deletion, and progressive tubulointerstitial fibrosis (8). Importantly, oxidative stress plays an important role in the pathogenesis of UUO (16,17). Several markers of oxidative stress, such as the oxidative stress response molecule heme oxygenase (HO)-1 and heat shock protein 27, are increased in UUO kidneys (16,29).The general paradigm is that oxidative stress occurs when the production of ROS is greater than the ability of cells to detoxify the produced ROS; indeed, increased concentrations of ROS have been observed in the obstructed kidney (35). Although oxidative stress is involved in the UUO model...

Human umbilical cord‐derived mesenchymal stem cells conditioned medium attenuate interstitial fibrosis and stimulate the repair of tubular epithelial cells in an irreversible model of unilateral ureteral obstruction

“…Recent studies have shown that ROS also plays a role in the UUO rat mode. 17 Our study also showed a significant increase in the amount of ROS in the kidneys of the UUO group compared to the sham group. MDA is the product of oxidative stress in vivo, which can reflect the level of oxidative stress.…”

“…Reactive oxygen species (ROS) plays an important role as a key signalling molecule in the progress of interstitial fibrosis and epithelial‐mesenchymal transition (EMT). Recent studies have shown that ROS also plays a role in the UUO rat mode . Our study also showed a significant increase in the amount of ROS in the kidneys of the UUO group compared to the sham group.…”

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney

“…Potentially, we may have been able to detect anti-apoptotic effects in a more chronic obstruction model, but further studies would be needed to test this. Antioxidants can ameliorate UUO-associated injury, as we have previously demonstrated that the antioxidants NADPH oxidase inhibitor diphenyleneiodonium (DPI) and the complex I inhibitor rotenone (ROT) prevented renal damage in response to 3dUUO42. Our current data suggest that metformin can upregulate NQO1 and HO-1, which might reduce ROS in response to obstructive nephropathy.…”

Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

“…DRI may also provide additional protection over other RAS inhibitors by interfering with the enhanced catalytic activity of (pro)renin after the binding of these molecules to the (pro)renin receptor (43). Further investigations are needed to clarify whether various potential signaling pathways, as seen in a recent study [e.g., cyclooxygenase-PGE 2 and ROS (38)] are involved in AQP2 regulation after UUO in response to DRI, ARB, or ACE inhibitor. A very recent study (13), however, showed that in contrast to an ACE inhibitor, aliskiren partitions to and is retained in kidneys, where aliskiren was found to localize not only in afferent arteries but also in the distal nephron and collecting ducts (13).…”