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Abstract: FR-PO134

Diverse Associations Between Oxidative Stress and Thromboxane A2 in Hypertensive Glomerular Injury

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Nakano, Yukihito, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
  • Nakatani, Yoshihisa, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
  • Takami, Masahiro, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
  • Arima, Shuji, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
Background

In addition to lowering blood pressure, therapeutic strategies to ameliorate hypertensive renal injury need to be established. In this study, we studied the possible contribution of thromboxane A2 (TXA2) which contributes to impaired renal hemodynamics under pathological conditions and potently stimulates reactive oxygen species generation, to the development of regional heterogeneity in hypertensive glomerular injury. We examined the impact of the inhibition of TXA2 synthesis in relation to its antioxidant effects on regional glomerular injury.

Methods

Experiments were performed using male stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar–Kyoto rats (WKY) at 5, 10 and 15-week age, respectively. We investigated systolic blood pressure (SBP), the degree of glomerular injury (glomerular sclerosis index: GSI), urinary albumin excretion (UAE), serum creatinine concentration (Cr), urinary 8-OHdG excretion, thromboxane synthase (TXAS) and heme oxygenase-1 (HO-1) gene expression. We also evaluated difference in GSI and each gene expression between superficial and juxtamedullary glomeruli. Then we investigated the effect of tempol (an intracellular antioxidant) and ozagrel (TXAS inhibitor).

Results

Juxtamedullary glomeruli showed higher GSI after 10 weeks of age in both rats. TXAS and HO-1 mRNA expression was enhanced in both superficial and juxtamedullary glomeruli in SHRSP compared with that in age-matched WKY. Notably in juxtamedullary glomeruli, TXAS expression was progressively enhanced as rats grow. Neither tempol nor ozagrel had any effect on SBP or Cr in SHRSP. Ozagrel but not tempol improved GSI in both superficial and juxtamedullary glomeruli. Tempol significantly increased TXAS expression in superficial but not juxtamedullary glomeruli, whereas ozagrel suppressed it.

Conclusion

Under the established severe hypertension, the glomerular injury as well as TXAS expression was augmented. Since these changes were attenuated by ozagrel but not tempol, the TXA2–TPR pathway and oxidative stress participate and interact together to promote hypertensive glomerular injury. Moreover, our results indicated that TXA2 inhibition may be a better therapeutic target than ROS inhibition to inhibit the aggravation of hypertensive glomerular injury at an advanced stage.