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(American Journal of Pathology. 2001;159:1895-1904.)
© 2001 American Society for Investigative Pathology

Regular Articles

Renal Tubulointerstitial Damage Caused by Persistent Proteinuria Is Attenuated in AT1-Deficient Mice

Role of Endothelin-1

Yusuke Suzuki*, Oscar Lopez-Franco*, Dulcenombre Gomez-Garre{ddagger}, Nuria Tejera*, Carmen Gomez-Guerrero*, Takeshi Sugaya{dagger}, Rosa Bernal{ddagger}, Julia Blanco§, Luis Ortega§ and Jesús Egido*

From the Renal and Vascular Laboratory,*
Fundación Jiménez Díaz, Autonoma University, Madrid, Spain; the Departments of Internal Medicine{ddagger}
and Pathology,§
Hospital Clinico, Complutense University, Madrid, Spain; and the Discovery Research Laboratory,{dagger}
Tanabe Seiyaku Company, Limited, Osaka, Japan

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-ß, and matrix mRNA expression and mortality. AT1(-/-) also showed a significant diminution in the activation of the transcriptional factors nuclear factor-{kappa}B 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.




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