Renal damage is not improved by blockade of endothelin receptors in primary renin-dependent hypertension.
OBJECTIVE
Secondary activation of the renin-angiotensin system plays a major role in the progression of chronic nephropathies, and blockade of endothelin (ET) receptors has been shown to confer nephroprotection in experimental models of proteinuric renal disease. We tested the nephroprotective potential of selective endothelin A receptor (ETA) and non-selective ETA and endothelin B (ETA/B) receptor blockade in the TGR(mRen2)27 transgenic rat model with renin-dependent hypertension (Ren2).


METHODS
Ren2 animals were treated between 10 and 30 weeks of age with the selective ETA receptor antagonist darusentan (Ren2-ETA) and the ETA/B receptor antagonist Lu420627 (Ren2-ETA/B), and compared with transgene negative Sprague-Dawley (SD) controls. Since the elevated systolic blood pressure in Ren2 was not affected in either Ren2-ETA or Ren2-ETA/ETB, an additional Ren-2 group was treated with a non-antihypertensive dose of the angiotensin II type 1 receptor blocker eprosartan (Ren2-AT1).


RESULTS
During the 20-week observation period 35% of untreated Ren2, 30% of Ren2-ETA/B, 50% of Ren2-ETA, and 83% of Ren2-AT1 animals survived compared with 100% of SD rats. Renal endothelin-1 mRNA expression and proteinuria (4.1-fold) were significantly elevated in Ren2 compared with SD rats (P < 0.05, respectively). Proteinuria was normalized to SD control levels in Ren2-AT1 (P < 0.05) but increased further in Ren2-ETA (7.7-fold) and Ren2-ETA/B (15-fold) (P < 0.05, respectively). Glomerulosclerosis, tubulointerstitial damage and renal osteopontin mRNA expression were reduced in Ren2-AT1 (P < 0.05, respectively) but remained unchanged or increased further in Ren2-ETA and Ren2-ETA/B compared with Ren2.


CONCLUSIONS
ET receptor blockade fails to improve renal damage and mortality in primary renin-dependent hypertension.
Rothermund
Lars
L
Institut für Klinische Pharmakologie und Toxikologie and Medizinische Klinik IV Nephrologie, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Freie Universität Berlin, Germany.
Kossmehl
Peter
P
Neumayer
Hans-H
HH
Paul
Martin
M
Kreutz
Reinhold
R
D000179:Acrylates / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000187:drug effects; D000072396:Endothelin-Converting Enzymes; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D006977:Hypertension, Renal / Q000378:metabolism* / Q000503:physiopathology*; D007093:Imidazoles / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008666:Metalloendopeptidases; D008955:Models, Cardiovascular; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D053495:Osteopontin; D011507:Proteinuria / Q000652:urine; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D013876:Thiophenes
D000179:Acrylates; D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D007093:Imidazoles; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D013876:Thiophenes; D053495:Osteopontin; C068373:eprosartan; D016282:Aspartic Acid Endopeptidases; D012083:Renin; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes