Antioxidant expression in experimental hydronephrosis: Role of mechanical stretch and growth factors

Sharon D. Ricardo, Guohua Ding, Michael Eufemio, Jonathan R. Diamond

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Abstract

We assessed whether levels of renal reactive oxygen species (RES) 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)-β 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,Zn-SOD) mRNA from 96-h UUO rats showed a 5.5-fold (P < 0.001 and 5.0-fold (P < 0.001) decrease, respectively, compared with 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-h UUO kidney slice cultures. In situ hybridization and immunohistochemistry showed Cu. Zn-SOD and catalase mRNA and protein transcription expressed in proximal tubules of UUO and CUK specimens. Catalase mRNA levels were markedly downregulated following a 1-h exposure of isolated proximal tubules to TGF-β (0.1-10 ng) and IL-1 (1-5 ng), in comparison to control proxima/tubular suspensions. OKC subjected to cyclic mechanical stretch for 1-24 h had marked decrements in catalase mRNA levels, compared with unstretched cells at the same time point. These results indicate that a primary downregulation of proximal tubular Cu,Zn-SOD and catalase expression develops in the proxima] 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 downregulation of catalase mRNA expression, together with increased oxidant stress in the rat renal cortex post-UUO, may amplify the proinflammatory state of experimental hydronephrosis culminating in tubulointerstitial injury and fibrosis.

Original languageEnglish
Pages (from-to)789-798
Number of pages10
JournalAmerican Journal of Physiology-Renal Physiology
Volume272
Issue number6 41-6
Publication statusPublished - 22 Sep 1997
Externally publishedYes

Keywords

  • Catalase
  • Cyclic mechanical stretch
  • Superoxide dismutase
  • Transforming growth factor-β
  • Unilateral ureteral obstruction

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