Mechanisms underlying the ameliorative property of lisinopril in progressive mesangioproliferative nephritis.
The present study was performed to clarify the mechanism underlying the beneficial effects of lisinopril on chronic glomerulonephritis. Chronic glomerulonephritis was induced by a single injection of E30 monoclonal antibody (E30) recognizing Thy-1.1 antigen to unilaterally nephrectomized rats. E30 injection resulted in persistent massive proteinuria with a decrease in anionic charge sites on the glomerular basement membrane (GBM) at 8 weeks. Also, renal tissue from rats treated with E30 showed typical glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril exerted a potent antiproteinuric effect and suppressed the progression of both glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril recovered the reduced number of anionic charge sites on GBM, accounting for the positive action against massive proteinuria. Immunostaining for desmin revealed that lisinopril treatment prevented the injury of glomerular epithelial cells (GECs) occurring in the chronic nephritic stage. Also, the level of gene expression of transforming growth factor-beta (TGF-beta) and plasminogen activator inhibitor-1 (PAI-1) in the renal cortex were reduced, suggesting that lisinopril improved extracellular matrix (ECM) metabolism. These results indicated that proteinuria in Thy-1.1 antibody-induced chronic nephritis is associated with a decrease in anionic charge sites on GBM, and that the antiproteinuric effect of lisinopril is attributable to protection against GEC damage. Suppression of TGF-beta and PAI-1 expression contributed to the preventive effect of lisinopril on ECM deposition in renal tissue.
Shionogi Discovery Research Laboratories, Shionogi & Co., Toyonaka-City, Osaka, Japan. toshihiro.shinosaki@shionogi.co.jp
Toshihiro
T
Shinosaki
Ikuko
I
Miyai
Yasuharu
Y
Nomura
Tatsuo
T
Kobayashi
Norio
N
Sunagawa
Hidetake
H
Kurihara
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000648:ultrastructure; D017706:Lisinopril / Q000627:therapeutic use*; D008297:Male; D008854:Microscopy, Electron; D009393:Nephritis / Q000188:drug therapy*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017706:Lisinopril