Renal tubulointerstitial damage caused by persistent proteinuria is attenuated in AT1-deficient mice: role of endothelin-1

Am J Pathol. 2001 Nov;159(5):1895-904. doi: 10.1016/S0002-9440(10)63036-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Bosentan
  • Endothelins / antagonists & inhibitors
  • Extracellular Matrix / metabolism
  • Isoquinolines / pharmacology
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / etiology
  • Kidney Diseases / urine
  • Kidney Tubules / pathology*
  • Kinetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout / genetics
  • NF-kappa B / physiology
  • Proteinuria / chemically induced
  • Proteinuria / complications
  • Proteinuria / metabolism
  • Proteinuria / pathology*
  • Quinapril
  • RNA, Messenger / metabolism
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin / deficiency*
  • Receptors, Angiotensin / genetics
  • Reference Values
  • Serum Albumin, Bovine
  • Sulfonamides / pharmacology
  • Tetrahydroisoquinolines*
  • Transcription Factor AP-1 / physiology
  • Transforming Growth Factor beta / genetics

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Endothelins
  • Isoquinolines
  • NF-kappa B
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Sulfonamides
  • Tetrahydroisoquinolines
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • Serum Albumin, Bovine
  • Bosentan
  • Quinapril