EXPRESSION OF ENDOTHELIN-1 AND ENDOTHELIN-3 IN THE RAT-KIDNEY

Endothelins (ETs) 1 and 3 are expressed in the rat kidney, but the fac tors that regulate this expression remain unknown. To try to understan d what these might be, we have measured the renal levels of ET-1 and E T-3 mRNAs by the ribonuclease protection-assay technique after a numbe r of clearly defined renal/hemodynamic insults. 1) Six hours after the induction of hemorrhagic anemia and hypotension, there was a threefol d increase in ET-1 mRNA and a simultaneous threefold decrease in ET-3 mRNA. This indicates that, in this situation, these two ET isoforms ar e differentially controlled and emphasizes the need for assay techniqu es capable of distinguishing between them. 2) One day after applicatio n of a 0.2-mm clip to the left renal artery, there was a >2.5-fold ind uction of ET-1 mRNA in that kidney, which persisted for 10 days. A sma ller rise in ET-1 mRNA was seen in the contralateral organ. After 2 da ys, ET-3 mRNA levels were reduced by similar to 50% in the clipped org an. Both ramipril (an angiotensin-converting enzyme inhibitor, 7.5 mg/ kg daily) and bosentan (a nonselective ET receptor antagonist, 100 mg/ kg daily) substantially reduced the elevation in ET-1 mRNA seen in the clipped kidney after 2 days, suggesting that the generation of angiot ensin II and the action of ET itself are involved in the mechanism by which clipping stimulates ET-1 expression. By contrast, ramipril, but not bosentan, prevented the reduction in ET-3 mRNA levels. 3) Renal de nervation, dietary salt restriction, or diuretic treatment (furosemide ) did not alter renal expression of ET-1 or ET-3. 4) ET-2 mRNA was not detected in any sample from normal or experimental kidney.