Targeted deletion of angiotensin II type 1A receptor does not protect mice from progressive nephropathy of overload proteinuria

Ariela Benigni, Daniela Corna, Carla Zoja, Lorena Longaretti, Elena Gagliardini, Norberto Perico, Thomas M. Coffman, Giuseppe Remuzzi

Research output: Contribution to journalArticle

Abstract

In experimental and human renal diseases, progression is limited by angiotensin-converting enzyme inhibitors. Whether renoprotection was due to their capacity of reducing proinflammatory and profibrotic effects of angiotensin II (Ang II) or limiting proteinuria and its long term toxicity is debated. For dissecting the relative contribution of Ang II and proteinuria to chronic renal damage, the protein-overload proteinuria model was used in genetically modified mice lacking the major isoform of murine AT1 receptor (AT1A). Uninephrectomized AT1A+/+ and -/- mice received a daily injection of BSA or saline for 4 or 11 wk. AT1A-/-BSA mice acquired a renal phenotype of proteinuria and renal glomerular and tubulointerstitial lesions, albeit attenuated with respect to AT 1A+/+BSA. Administration of the calcium channel blocker lacidipine to reduce BP of AT1A+/+BSA mice to levels of AT1A-/-BSA translated into comparable values of protein excretion rate and glomerular and tubulointerstitial injury in both strains. These results confirm that the toxic effect of protein trafficking on renal disease progression is not necessarily dependent on Ang II to the extent that targeted deletion of AT1A does not prevent disease progression. A role of Ang II via AT1B or AT2 receptors is still a possibility that cannot be ruled out by the present experimental approach. These findings provide a clear rationale for specifically targeting proteinuria in pharmacologic interventions of chronic nephropathies.

Original languageEnglish
Pages (from-to)2666-2674
Number of pages9
JournalJournal of the American Society of Nephrology
Volume15
Issue number10
DOIs
Publication statusPublished - Oct 2004

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'Targeted deletion of angiotensin II type 1A receptor does not protect mice from progressive nephropathy of overload proteinuria'. Together they form a unique fingerprint.

  • Cite this