title: Angiotensin II receptor blockade inhibits acute glomerular injuries with the alteration of receptor expression.
abstract: Angiotensin II receptor blockade (ARB) suppresses the progression of chronic kidney disease. However, the renoprotective effect of ARB in the active phase of glomerulonephritis (GN) has not been evaluated in detail. We examined the alteration of angiotensin II receptors' expression and the action of ARB on acute glomerular injuries in GN. Thy-1 GN was induced in rats that were divided into three groups (n=7, in each group); high dose (3 mg/kg/day) or low dose (0.3 mg/kg/day) olmesartan (Thy-1 GN+HD- or LD-ARB group), and vehicle (Thy-1 GN group). Renal function and histopathology were assessed by week 2. In the Thy-1 GN group, diffuse mesangiolysis and focal aneurysmal ballooning developed by day 3. Marked mesangial proliferation and activation progressed with glomerular epithelial injury. We confirmed that both angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) were expressed on glomerular endothelial, mesangial, epithelial cells, and macrophages, and increased 7 days after disease induction. However, ARB treatment caused a decrease in AT1R and a further increase in AT2R expression in glomeruli. ARB prevented capillary destruction and preserved eNOS expression after diffuse mesangiolysis. Mesangial proliferation and activation was suppressed markedly with low levels of PDGF-B expression. Glomerular desmin expression, which is a marker for injured glomerular epithelial cells, was diminished significantly with retained expression of nephrin and podoplanin. Glomerular macrophage infiltration was also inhibited. Proteinuria was suppressed significantly. Furthermore, these effects of ARB showed dose dependency. These results provide insights that ARB affects individual glomerular cells and macrophages through angiotensin II receptors, with the alteration of both AT1R and AT2R expressions, and leads to inhibition of the acute destructive and proliferative glomerular lesions in GN.
authors.affiliation: Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mii
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Yukinari
authors.initials: Y
authors.lastname: Masuda
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ishizaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iino
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Katayama
authors.forename: Yuh
authors.initials: Y
authors.lastname: Fukuda
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000077214:Becaplermin; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects*; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011507:Proteinuria / Q000517:prevention & control; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D018800:Thy-1 Antigens / Q000276:immunology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D015415:Biomarkers; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D018800:Thy-1 Antigens; D000804:Angiotensin II; D000077214:Becaplermin; C437965:olmesartan