The effects of ZENECA ZD8731, an angiotensin II antagonist, on renin expression by juxtaglomerular cells in the rat: comparison of protein and mRNA expression as detected by immunohistochemistry and in situ hybridization.
Changes in the mRNA and protein expression of renin-secreting cells in the juxtaglomerular apparatus (JGA) were examined in the rat following administration of ZENECA ZD8731, an angiotensin II receptor antagonist. Doses of 0 or 90 mg/kg were administered daily by gavage for 26 wk. JGA hypertrophy was apparent in histological sections. Immunohistochemistry demonstrated an increase in the number of renin-containing cells in both the afferent arterioles and the interlobular arteries. Similarly, renin mRNA expression, demonstrated by in situ hybridization, had extended to more proximal segments of the afferent arterioles and was also present in efferent arterioles and interlobular arteries. In conclusion, JGA hypertrophy occurred as a result of antagonism of the angiotensin II receptor. Associated with JGA hypertrophy was increased expression of both renin and renin mRNA, indicative of stimulated renin synthesis caused by an exaggerated pharmacological response of renin-secreting cells to the loss of feedback inhibition by angiotensin II.
Doughty
S E
SE
Safety of Medicines Department, ZENECA Pharmaceuticals, Macclesfield, Cheshire, England.
Ferrier
R K
RK
Hillan
K J
KJ
Jackson
D G
DG
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007606:Juxtaglomerular Apparatus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011506:Proteins / Q000032:analysis; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D011506:Proteins; D011804:Quinolines; D012333:RNA, Messenger; D000804:Angiotensin II; C081112:ICI D8731; D012083:Renin