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-β, and matrix mRNA expression and mortality. AT1(−/−) also showed a significant diminution in the activation of the transcriptional factors nuclear factor-κB 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.