Antioxidant expression in experimental hydronephrosis: role of
mechanical stretch and growth factors.
Ricardo, Sharon D., Guohua Ding, Michael Eufemio, and Jonathan R.
Diamond.
Departments of Medicine, Surgery, and Cellular and Molecular
Physiology, The Milton S. Hershey Medical Center, Pennsylvania State
University College of Medicine, Hershey, PA 17033
APStracts 4:0047F, 1997.
We assessed whether levels of renal reactive oxygen species (ROS) and
antioxidant enzymes are perturbed in rats following unilateral
ureteral obstruction (UUO). The mechanism of catalase perturbation
was investigated using proximal tubule suspensions following
stimulation with transforming growth factor (TGF)-b and interleukin
(IL)-1 and in a proximal tubular cell line (OKC) subjected to cyclic
mechanical stretch which mimics the early hydrodynamic derangement
after UUO. Levels of catalase and copper-zinc superoxide dismutase
(Cu-ZnSOD) mRNA from 96 hour UUO rats showed a 5.5-fold
(p<0.001) and 5.0-fold (p<0.001) decrease,
respectively, compared to the contralateral unobstructed kidney
(CUK). Levels of superoxide anion and hydrogen peroxide showed a
significant 1.8-fold (p<0.0001) and 14.0-fold
(p<0.0001) increase, respectively, in 96 hour UUO kidney-slice
cultures. In situ hybridization and immunohistochemistry showed Cu
-ZnSOD and catalase mRNA and protein transcription expressed in
proximal tubules of UUO and CUK specimens. Catalase mRNA levels were
markedly down-regulated following a 1 hour exposure of isolated
proximal tubules to TGF-b (0.1-10 ng) and IL-1 (1-5 ng), in
comparison to control proximal tubular suspensions. OKC subjected to
cyclic mechanical stretch for 1 to 24 hours had marked decrements in
catalase mRNA levels, compared to unstretched cells at the same time
point. These results indicate that a primary down-regulation of
proximal tubular Cu-ZnSOD and catalase expression develops in the
proximal tubules of UUO with consequent increments in cortical
oxidant levels. These findings suggest that either an early
mechanical disturbance produced by UUO, or local tubular generation
of cytokines, can reduce tubular catalase expression. The down
-regulation of catalase mRNA expression, together with increased
oxidant stress in the rat renal cortex post-UUO may amplify the pro
-inflammatory state of experimental hydronephrosis culminating in
tubulointerstitial injury and fibrosis.
Received 2 August 1996; accepted in final form 27 February 1997.
APS Manuscript Number F235-6.
Article publication pending Am. J. Physiol. (Renal Physiology).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 21 March 1997