The Selective TP Receptor Antagonist, S18886 (Terutroban), Attenuates Renal Damage in the Double Transgenic Rat Model of Hypertension

Abstract

Background/Aims: Thromboxane receptors play a decisive role in the renovascular actions of angiotensin II. We studied the efficacy of the selective thromboxane receptor antagonist, S18886, in the retardation of renal damage in the double transgenic rats (dTGR), harboring human renin and angiotensinogen genes. Methods: dTGR were gavaged daily with either S18886 (30 mg/kg/day, n = 12), or placebo (dTGR-Plac, tap water, n = 14) for 3 weeks. Matched Sprague-Dawley rats (n = 10) served as controls. Results: The dTGR-Plac had higher systolic blood pressure (1.7-fold) than controls, and developed profound renal damage with significantly higher proteinuria (6.9-fold), polyuria (2.3-fold), index of glomerulosclerosis (+58%), and tubulointerstitial (+47%) and vascular damage scores (+19%). Creatinine concentration and the mesangiolysis index remained unchanged. In dTGR, S18886 slightly lowered the blood pressure (162 ± 15 vs. 149 ± 13 mm Hg, not significant) and improved proteinuria (558 ± 218 vs. 136 ± 71 mg/µmol creatinine, p < 0.01), polyuria and renal morphology (glomerulosclerosis index: 0.79 ± 0.05 vs. 0.66 ± 0.13, p < 0.01; tubulointerstitial damage index: 1.82 ± 0.22 vs. 1.49 ± 0.27, p < 0.05; mesangiolysis index: 1.31 ± 0.18 vs. 0.36 ± 0.09, p < 0.01). Vascular damage score and plasma creatinine were not influenced. S18886 did not alter measured markers of oxidative stress. Conclusion: The data present the first evidence that thromboxane receptor inhibition ameliorates angiotensin II-induced nephropathy.

TP Receptors and Oxidative Stress

“…This was demonstrated directly by the fact that diabetic animals treated with aspirin did not show any benefit observed on either atherosclerotic lesions (unpublished studies) or nephropathy36 that was seen in the diabetic animals treated with S18886. The protective renal actions of S 18886 have also been observed in the uni-nephrectomized obese Zucker rat 37, and the TP antagonist attenuated renal damage in the double transgenic hypertensive rat harboring the human renin and angiotensinogen genes 38. Thus, protective renal actions of S 18886 extend to both type 1 and type 2 diabetes and renovascular hypertension, point out the role of TP receptors in these pathologies, and are particularly advantageous in treating complex cardiovascular disease that is usually of a systemic nature.…”

Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease

“…To date, there have been no candidate genes for kidney injury identified via linkage analysis and subsequently followed up using a transgenic approach. However, there are a number of transgenic models, such as Tg human renin and/or angiotensinogen genes that exhibit increased hypertension and renal injury 56 or Tg Ren2, 57,58 among many others. Recently, one group developed a transgenic rat with podocyte-specific expression using the human podocin promoter (NPHS2).…”

TP Receptor Antagonism: A New Concept in Atherothrombosis and Stroke Prevention

“…A model of angiotensin II-induced nephropathy in hypertensive transgenic rats was used to show that terutroban was able to strikingly improve the functional and morphological parameters of the nephropathy [23]. Michel et al [24] found an increased responsiveness of TP receptors in diabetic apolipoprotein E-deficient mice.…”