End-organ damage in hypertensive transgenic Ren-2 rats: influence of early and late endothelin receptor blockade

The rat strain transgenic for the murine Ren-2 renin gene (TGR)is defined as a monogenic model of angiotensin II-dependenthypertension with endogenous activation of the renin-angiotensinsystem. Homozygous males TGR develop malignant hypertensionwith a strong salt-sensitive component. These animals showsevere hypertension, proteinuria and high mortality.Morphological changes of renal parenchyma correspond tochronic ischemic glomerular changes. Heterozygous TGR developonly mild hypertension and thus provide a more suitable model ofhypertension regarding to clinical studies. Within the renalparenchyma, secondary focal segmental glomerulosclerosis(FSGS) predominates. High-salt diet in heterozygous animalsinduces transition from benign to malignant phase ofhypertension. In this case, ischemic glomerular changes aresuperimposed on preexisting secondary FSGS. In the regressionmodel of hypertension (late-onset treatment) the effect of saltintake is attenuated. In homozygous TGR, early selective ETAreceptor blockade decreased blood pressure and amelioratedend-organ damage. Late selective ETA receptor blockade reducedpodocyte injury despite final severe hypertension. Survival ratewas markedly improved in both regimens with ETA selectiveblockade, while there was only partial improvement with earlynon-selective blockade. Both bosentan and atrasentan decreasedET-1 levels in both regimens. In heterozygous TGR, early andlate ETA treatment substantially while ETA/ETB treatment partiallyimproved survival rate. Significant effect on BP was found withearly and late ETA blockade, while ETA/ETB blockade had noeffect. Bosentan and atrasentan similarly decreased ET-1 levelson both regimens. In conclusion, selective ETA receptor blockadeis superior to nonselective ETA/ETB receptor blockade inattenuating hypertension and end-organ damage. Its effect ismore pronounced when applied early in the life.