title: Renal tubulointerstitial damage caused by persistent proteinuria is attenuated in AT1-deficient mice: role of endothelin-1.
abstract: Using angiotensin II (AngII) type 1A receptor-deficient mice [AT1(-/-)], in which we induced protein overload nephropathy, we explored the potential implication of AngII and endothelin-1 (ET-1) in the tubulointerstitial damage because of persistent proteinuria. At day 7, AT1(-/-) showed marked proteinuria to a similar extent to that of wild-type mice (WT). However, at day14, AT1(-/-) had significantly less proteinuria, renal damage, transforming growth factor-beta, and matrix mRNA expression and mortality. AT1(-/-) also showed a significant diminution in the activation of the transcriptional factors nuclear factor-kappaB and AP-1. Unexpectedly, AT1(-/-) had a higher interstitial infiltration than WT. The administration of the angiotensin-converting enzyme inhibitor quinapril to WT caused a marked improvement in proteinuria and renal lesions, resembling that seen in untreated AT1(-/-). However, the interstitial infiltration persisted in AT1(-/-) when treated with quinapril. Because ET-1 may participate in the recruitment of mononuclear cells, we also studied the implication of this peptide. AT1(-/-) had a significantly higher ET-1 expression in tubular epithelial cells than WT. The administration of the dual ETA/ETB antagonist bosentan to AT1(-/-) considerably reduced the interstitial infiltrates. Bosentan also exerted a beneficial effect on proteinuria, renal lesions, and mortality in WT. These data show that in overload nephropathy, proteinuria and renal lesions are, to a large extent, AngII-dependent. The up-regulation of ET-1 in tubular epithelial cells in AT1(-/-), associated with interstitial infiltrates, suggests that the combination of drugs interfering with both vasopeptides may be of therapeutic interest in renal diseases with severe proteinuria and tubulointerstitial damage.
authors.affiliation: Renal and Vascular Laboratory, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: O
authors.initials: O
authors.lastname: Lopez-Franco
authors.forename: D
authors.initials: D
authors.lastname: Gomez-Garre
authors.forename: N
authors.initials: N
authors.lastname: Tejera
authors.forename: C
authors.initials: C
authors.lastname: Gomez-Guerrero
authors.forename: T
authors.initials: T
authors.lastname: Sugaya
authors.forename: R
authors.initials: R
authors.lastname: Bernal
authors.forename: J
authors.initials: J
authors.lastname: Blanco
authors.forename: L
authors.initials: L
authors.lastname: Ortega
authors.forename: J
authors.initials: J
authors.lastname: Egido
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000077300:Bosentan; D016232:Endothelins / Q000037:antagonists & inhibitors; D005109:Extracellular Matrix / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000652:urine; D007684:Kidney Tubules / Q000473:pathology*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology; D011507:Proteinuria / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000077583:Quinapril; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000172:deficiency* / Q000235:genetics; D012016:Reference Values; D012710:Serum Albumin, Bovine; D013449:Sulfonamides / Q000494:pharmacology; D044005:Tetrahydroisoquinolines; D018808:Transcription Factor AP-1 / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D016232:Endothelins; D007546:Isoquinolines; D016328:NF-kappa B; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D012710:Serum Albumin, Bovine; D000077300:Bosentan; D000077583:Quinapril